Acute lymphoblastic leukemia of T progenitors: From biology to clinics

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It presents an early peak at 4 or 5 years of age (incidence rate of 4–5 per 100,000 persons/year) an incidence decrease in young adults, and a slight increase after 50 years of age (incidence rate of up to 2 per 100,000 persons/year). The cure rate is lower in adults than in children, with a long-term disease-free survival of approximately 80% in children and 35–45% in adults (<a href="http://www.seer.cancer.gov/statistics">www.seer.cancer.gov/statistics</a>). Specifically, the T-ALL corresponds to 15% of childhood acute leukemias and 25% of the adult ones. The curve of incidence presents only one peak located in the child/adult boundary and the survival does not differ from that of the precursors B-ALL. This T subtype is characterised by presenting a greater heterogeneity and genetic complexity, making it attractive for research, despite being a rare ALL subtype.The purpose of this study is to summarise the latest scientific advances in T-ALL, at a basic level as well as at a clinical level, and show where the research is headed in this ALL subtype and which are the key items to resolve at medium–long term with the purpose of improving the treatment and survival of patients with this disease.Towards a molecular characterisation “a la carte”Variations in the number of gene copies in precursor T-acute lymphoblastic leukemiaIn these last years, the studies based on the use of large-scale and high-resolution genomic techniques have been of vital importance for the comprehension of ALL, and especially revealing in T-ALL. Since in 2005 Irving et al. demonstrated that through arrays of single nucleotide polymorphisms (SNP) loss of heterozygosity (LOH) could be successfully identified in ALL,<a class="elsevierStyleCrossRef" href="#bib0310">2</a> there have been numerous studies that involved new genes in the development of T-ALL through screening of copy number variations (CNV) with SNP arrays or with comparative genomic hybridisation arrays. Thus, focal alterations of copy number that imply a TAL1, LMO2, PTEN, FBXW7 and MYB deregulation, among others, have been identified<a class="elsevierStyleCrossRef" href="#bib0315">3</a> (<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Arrays of expressionFrom the comparative studies of the pattern of expression of human T-ALL samples and normal T cells at different stages of differentiation, a consensus has been reached regarding 3 big T-ALL subtypes that group the different subtypes based on the chromosomal abnormalities present in the leukemic cell: (a) early T-cell precursor (ETP), characterised by the absence of CD1a, CD4 and CD8 immunomarkers and the presence of myeloid or pluripotent cell markers such as CD117, CD34, HLA-DR, CD13, CD33, CD11b, or CD65<a class="elsevierStyleCrossRef" href="#bib0320">4</a>; (b) cortical subtype, characterised by the aberrant expression of the transcription factor family with a homeobox domain, such as TLX3, NKX2.1 and NKX2.2,<a class="elsevierStyleCrossRefs" href="#bib0325">5–7</a> and by the expression of the CD1, CD4 and CD8 immunomarkers<a class="elsevierStyleCrossRef" href="#bib0325">5</a> and Pre-T1 or Pre-T2/Pre-T3 (E),<a class="elsevierStyleCrossRef" href="#bib0330">6</a> and (c) mature subtype, characterised by the expression of the TAL oncogene,<a class="elsevierStyleCrossRefs" href="#bib0325">5–7</a> CD4, CD8 and CD3 immunomarkers<a class="elsevierStyleCrossRef" href="#bib0325">5</a> and T cell receptorαβ.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> In <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, there is a summary of the main chromosomal alterations that characterise these 3 molecular subtypes.Next-generation sequencingAnother great advance in the knowledge of new genes that participate in the development of T-ALL was produced with the development of the new next generation sequencing (NGS) platforms. This technique enables the detection of punctual mutations with very high sensitivity and LOH and CNV with very high resolution. <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the main genes with recurring punctual mutations that affect T-ALL. At the beginning of the year 2012, the Mullighan group, at the St. Jude Children's Research Hospital, published the first complete sequencing of the ALL genome performed in 12 samples of ETP type childhood T-ALL,<a class="elsevierStyleCrossRef" href="#bib0340">8</a> and they demonstrated that this ALL subtype presents activating somatic mutations in cytokines and genes that participate in the RAS pathway, such as NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF, as well as genetic alterations that inactivate genes that participate in the haematopoietic development, such as GATA3, ETV6, RUNX1, IKZF1 and EP300, and histone-modifying genes (EZH2, EED, SUZ12, SETD2 and EP300). It is worth mentioning that the mutational spectrum identified in the ETP leukemia was similar to that of the poor-prognosis acute myeloid leukemias (AML), with affected genes that define the pluripotent character of the myeloid cell.<a class="elsevierStyleCrossRef" href="#bib0340">8</a> Recently, another complete exome study in ETP leukemia samples in adults has identified mutations in the DNMT3A methyltransferase in 16% of the patients (10/68), a similar frequency to the one detected in AML. Moreover, mutations have been found in the FAT1 (25%) and FAT2 cadherins (20%), thus involving genes that participate in cell adhesion and in the interaction between stromal and leukemic cell.<a class="elsevierStyleCrossRef" href="#bib0345">9</a> Using this same technique, De Keersmaecker et al. identified mutations in the CNOT3 gene in 3.8% (8/211) of the T-ALL samples analysed. The mutations identified cause a lower gene expression, which evidences that CNOT3 could act as a tumour suppressor gene.<a class="elsevierStyleCrossRef" href="#bib0350">10</a> Moreover, mutations were identified in the RPL10 gene (5.2%, 11/211) and in the RPL5 gene (1.9%, 4/211). Both genes codify by ribosomal proteins that are part of the 60S ribosomal complex.<a class="elsevierStyleCrossRef" href="#bib0350">10</a> The recurring mutation most frequently observed in RPL10, a change of Arg98Ser amino acid, causes an increase of the proliferation and a defect in the ribosome biogenesis in lymphoid cells, which demonstrates that this mutation could help the leukemic cell decrease its translational and growth activity in favour of proliferation.Adult and childhood precursor T-acute lymphoblastic leukemiaAs the amount of genes involved in the T-ALL increases, and also does the number of samples analysed, adult and childhood T-ALLs are outlined as 2 differentiated subgroups. The wide sequencing study performed by the Cools group in 67 T-ALL samples at the time of diagnosis observed that the number of mutations in adults was 2.5 times higher than in children (21.0 versus 8.2), with a clear correlation between age and number of mutations. However, this fact did not imply any prognostic significance. Likewise, it was observed that adults presented mostly mutations in genes regulatory of the methylation pattern, such as KDM6A (4.5%, 3/67) and MAGEC3 (3.0%, 2/67), in transcriptional regulators, such as PHF6 (17.9%, 12/67), and in tumour suppressor genes, such as CNOT3 and FBXW7 (11.9%, 8/67).<a class="elsevierStyleCrossRef" href="#bib0350">10</a> Likewise, in the exome study performed by Neumann et al. in samples of adults with ETP T-ALL, specific mutations in methylation regulatory genes were also identified, such as DNMT3A methyltransferase.<a class="elsevierStyleCrossRef" href="#bib0345">9</a> In other respects, as stated before, in the exome study performed by De Keersmaecker et al., specific mutations in proteins that are part of the 60S ribosomal complex were identified in samples of childhood ALL.<a class="elsevierStyleCrossRef" href="#bib0350">10</a> All these data would evidence that the T-ALL pathogenesis in adults and children could be different. While in adults the epigenetic factors would have a determining role, in children the changes in the cellular metabolism and in the biosynthesis of organelles and macromolecules necessary for the generation of new cells would develop a key role in the tumour development. This is a new exploration field in T-ALL that we will see developing in the immediate future, with consequences at therapeutic level.A new protagonist in precursor T-acute lymphoblastic leukemia: micro-ribonucleic acidsWith the advance in the molecular knowledge of T-ALL, not only the identification of tumour suppressor genes and oncogenes was possible, but also the identification of mutations in non-codifying genes, such as micro-ribonucleic acids (miRNA). miRNAs are one of the most abundant regulatory molecules in multicellular organisms and they affect the expression of a great number of genes. The miR-17-92 cluster, and specifically the miR-19b, was the first described miRNA that was overexpressed in human samples of T-ALL.<a class="elsevierStyleCrossRef" href="#bib0355">11</a> Subsequently, the existence of a double clonal translocation of TCR/D locus in the chromosomal band 14q11 was described. This affected, on the one hand, NOTCH1, through the t(9;14)(q34;q11) translocation, and on the other hand, the miR-17-92 cluster, through t(13;14)(q32;q11). Shortly afterwards, it was observed that the coexpression of the active form of NOTCH1 and miR-19 in the mouse haematopoietic progenitors accelerated the NOTCH1-induced leukemia in the murine model, demonstrating the cooperation of this miRNA in T-ALL development. Moreover, the BIM, PTEN, PRKAA1, DOCK5 and PPP2R5E genes were identified as genes regulated by such miRNA.<a class="elsevierStyleCrossRef" href="#bib0360">12</a> In 2011, the first miRNA screening in T-ALL was published. Mavrakis et al. identified 5 miRNA (miR-19b, miR-20a, miR-26a, miR-92 and miR-223) capable of accelerating leukemia in a mouse T-ALL model, and they also observed that these miRNAs act cooperatively inhibiting tumour suppressor genes, such as PTEN, BIM and FBXW7.<a class="elsevierStyleCrossRef" href="#bib0365">13</a> The Baldus group, specialised in the molecular characterisation of ETP T-ALLs, observed the miR-221 and miR-222 overexpression, and the miR-151-3p, miR-19a, miR-20b, miR-342-3p, miR-363 and miR-576-3p underexpression through the analysis of miRNA expression arrays in samples of adults with ETP T-ALL. The aforementioned group also demonstrated that the miR-222 overexpression implied a decrease of the values of the ETS1 gene messenger RNA, which regulates the differentiation of macrophages, evidencing that the miR-222 overexpression in the ETP T-ALLs would imprint the myeloid character present in this subtype. Moreover, the group observed that the high expression of miRNA was positively associated with the expression of genes with prognostic impact in the ETP T-ALL.<a class="elsevierStyleCrossRef" href="#bib0370">14</a> It has recently been described that the miR-150 expression, a miRNA that has been widely studied in B cells, increases in CD4+ or CD8+ T cells and decreases in CD4+–CD8+ T cells (double-positive T cells, T-DP), and it is capable of regulating the NOTCH3 expression in T-DPs as well as in CD4+ or CD8+ T cells. Moreover, authors indicate a possible role of this miRNA in T-ALL since it regulates the proliferation and the apoptosis of T-cells cell lines.<a class="elsevierStyleCrossRef" href="#bib0375">15</a> In the mature subtype T-ALLs, that overexpress TAL1, it has been observed that the TAL1 oncogene expression causes a miR-223 overexpression and, in consequence, a deregulation of miRNA targets such as FBXW7, key tumour suppressor in the development of T-ALL.<a class="elsevierStyleCrossRef" href="#bib0380">16</a> Undoubtedly, this type of regulation will be described in other types of cancer. Finally, miR-142-3p, which is overexpressed in T-cell leukemias,<a class="elsevierStyleCrossRefs" href="#bib0365">13,17</a> has been related to a possible mechanism of glucocorticosteroid resistance, since it is capable of regulating the translation of the α glucocorticosteroid receptor isoform (GRα).<a class="elsevierStyleCrossRef" href="#bib0385">17</a>Clinical involvement: prognostic value of biomarkersThe method to assess if the information obtained in the basic investigation is clinically relevant is by correlating the data with the medical information from groups of patients included in homogeneous treatment protocols, and establishing the prognostic value of the different molecular markers. <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> summarises the molecular markers with prognostic values identified up to date. We can observe that although the number of markers with prognostic significance increases, the studies that obtain different, sometimes conflicting results also increase. The clearest example is the predictive value of the mutations in NOTCH1/FBWX7 in children. Two different groups, with 2 different treatment protocols (the English MRC UKALL-2003<a class="elsevierStyleCrossRef" href="#bib0390">18</a> and the German ALL-BFM 2000<a class="elsevierStyleCrossRef" href="#bib0395">19</a>) have confirmed the mutations in NOTCH1 as favourable prognosis marker in childhood T-ALL. Notwithstanding, the American Pediatric Oncology Group did not find predictive value in a study of 47 patients included in 5 different treatment protocols.<a class="elsevierStyleCrossRef" href="#bib0400">20</a> Likewise, the multicentre study performed by a French group, which included children treated with 2 different protocols (EORTC 5881/58951), observed that the NOTCH1 mutations only had favourable prognosis value in the early response to the treatment.<a class="elsevierStyleCrossRef" href="#bib0405">21</a> In the case of adults, the prognosis value of NOTCH1/FBWX7 is even more difficult to analyse because there are less studies and because there are contradicting results based on the different treatment protocols (LALA-94 and GRAALL03/05, from the French group,<a class="elsevierStyleCrossRefs" href="#bib0410">22,23</a> and protocols GMALL 05/93 and 06/99 from the German group<a class="elsevierStyleCrossRef" href="#bib0420">24</a>) (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Recently, a study performed with patients included in one protocol from the Eastern Cooperative Oncology Group (E2993ECOG) has confirmed the favourable prognosis value of the mutations in NOTCH1/FBWX7 in a series of 53 adult patients.<a class="elsevierStyleCrossRef" href="#bib0425">25</a> Finally, on the one hand, there is a variation of results associated with the use of samples coming from different treatment protocols within the same study, and, on the other hand, a different impact based on the application of different treatment protocols among the different work teams in T-ALL. Therefore, it is necessary to perform international cooperation studies that include different work teams with their respective treatment protocol to be able to clearly define the clinical involvement of the different molecular markers currently available.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Minimal residual diseaseThe analysis of the minimal residual disease (MRD), either via flow cytometry (for aberrant immunophenotypes), via detection of the polymerase chain reaction of fusion gene (for leukemias with T cell receptor [TCR] translocation or others), or TCR rearrangement, is the clearest and most potent existing prognostic factor of treatment response in T-ALL, both in children as well as in adults.<a class="elsevierStyleCrossRefs" href="#bib0430">26,27</a> This marker is very useful to follow-up on the patient's response to treatment and for the early detection of groups with high risk of relapse, with the possibility of adapting, and even anticipating, treatment in these patients.Relapse and clonal heterogeneityThe approaches at genomic scale have also helped design the clonal heterogeneity in T-ALL at the time of diagnosis. The importance of this subclonal heterogeneity has been recently manifested via the comparative analysis of the CNV of samples of childhood T-ALL at diagnosis and relapse.<a class="elsevierStyleCrossRef" href="#bib0440">28</a> Clappier et al. observed that even though leukemic cells at diagnosis and relapse share a great number of genetic lesions, at relapse, there are genetic mutations and/or alterations that are underrepresented in diagnosis samples. Thus, at the time of diagnosis, the leukemia would be composed of different subclones that would share the same preleukemic common ancestor, but only one or a few would be capable of acquiring a selective advantage in a determined microenvironment (niche) and proliferate until developing the leukemia. The relapse would mainly be composed of clones underrepresented in diagnosis, which have been selected during treatment. The mutational screening of pairs of samples of patients with childhood ALL at diagnosis and relapse via NGS identified that the NT5C2 gene was specifically mutated at relapse.<a class="elsevierStyleCrossRef" href="#bib0445">29</a> Gene sequencing in a greater number of patients confirmed that the mutations in NT5C2 were found in 19% of the samples of T-ALL in relapse. These mutations create resistance to 6-mercaptopurine and 6-thioguanine, 2 analogues of nucleoside used in the treatment of T-ALL, which demonstrated for the first time that the leukemia developed in relapse is resistant to treatment.<a class="elsevierStyleCrossRef" href="#bib0445">29</a> A similar study published by Meyer et al. was capable of detecting mutations in NT5C2 at diagnosis in 2/7 samples analysed, with a frequency of mutated alleles of 0.01% and 0.02%, respectively, which indicates that in some cases the clone resistant to treatment already exists at diagnosis at a very low frequency.<a class="elsevierStyleCrossRef" href="#bib0450">30</a> These data evidence that the treatment at diagnosis and relapse should be different. Notwithstanding, they do not enable the prediction or anticipation of the resistant clones before starting treatment. Besides, they question the origin of the clone resistant to treatment in those cases in which it is not detected at diagnosis. Maybe the generation of subclones would be a much more dynamic process clearly influenced by the selective pressures of the microenvironment, such as treatment.TreatmentMany of the drugs used in the treatment of ALL were developed before the 1970s. Since then, the treatment of ALL has not ceased to improve until achieving a survival rate close to 90% in childhood ALL, and in adults, between 30% and 40%. This has happened due to the numerous treatment protocols developed by different work teams in ALL, in which the use of different drug combinations, their doses and sequences of administration have been optimised. Added to this, it is worth mentioning the ability to monitor treatment response through MRD detection and to adapt the treatment based on the response. Moreover, the identification of specific risk groups based on the ALL molecular characteristics, such as the Philadelphia chromosome ALLs, has enabled the administration of more specific and efficient treatments. However, using treatment strategies alike in children and adults, the cure rate in the latter is still low. This is due to the fact that the disease is genetically more heterogeneous and complex, with a greater presence of genetic variables of bad prognosis, and because, in many cases, the adult does not tolerate the treatment intensity and density administered to children.Standard treatmentPatients with T-ALL, except for the adults with cortical subtype and less than 100×109 leukocytes/L in blood at the time of diagnosis, are included in the high-risk protocols, that are generally the same as or very similar to those of the precursor B-ALL, which is noteworthy since they are diseases that are different at genetic level. Notwithstanding, there are differences between treatment protocols among adults and children, since the therapeutic regime in the latter is more intensive, using a higher frequency of cycles and higher cytostatic concentrations. In young adults, there is a tendency to apply paediatric protocols and this has implied an improvement in global survival.<a class="elsevierStyleCrossRef" href="#bib0455">31</a> However, the application of these therapeutic regimes is only feasible in patients with a maximum age of 45–55 years, since if they are applied in older patients, the increase of treatment-related mortality neutralises the positive effect of the treatment itself.<a class="elsevierStyleCrossRef" href="#bib0455">31</a> In general, adult patients with T-ALL and high-risk criteria are treated with chemotherapy followed by allogeneic haematopoietic progenitor cell transplantation.New treatmentsSome of the molecular alterations identified in ALL have been used as targets of new specific drugs. The most paradigmatic example is the BCR-ABL1 fusion gene and the development of tyrosine-kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib and ponatinib, among others), some of which have been successfully assayed in children and adults with ALL with the aforementioned translocation.<a class="elsevierStyleCrossRefs" href="#bib0460">32,33</a> A minority of the patients with T-ALL presents genetic alterations that affect the ABL1 gene, such as NUP214-ABL1, EML1-ABL1 and ETV6-ABL1, for which the efficiency of these inhibitors is also being investigated.<a class="elsevierStyleCrossRef" href="#bib0470">34</a>One of the drugs approved for the treatment of resistant T-ALL or T-ALL in second or subsequent relapse is nelarabine. This analogue of deoxyguanosine, which is specifically accumulated in T cells, has offered promising results in phase I and II studies performed in adults as well as in children in relapse.<a class="elsevierStyleCrossRef" href="#bib0475">35</a> The neurological toxicity is the most relevant toxicity.<a class="elsevierStyleCrossRef" href="#bib0475">35</a> The Children's Oncology Group demonstrated that the inclusion of nelarabine in the intensive treatment with chemotherapy in high-risk patients diagnosed with de novo T-ALL was feasible, with promising results.<a class="elsevierStyleCrossRef" href="#bib0480">36</a> The Group has included this combination in its current treatment protocol (COG AALL0434).ImmunotherapyA great step forward in the treatment of ALL has been the incorporation of specific therapy via monoclonal antibodies, such as anti-CD20 (rituximab), anti-CD19 (blinatumomab, which is also anti-CD3), anti-CD52 (alemtuzumab), anti-CD22 (epratuzumab and inotuzumab ozogamicin) and anti-CD33 (gemtuzumab ozogamicin), among others.<a class="elsevierStyleCrossRef" href="#bib0485">37</a> Most of these monoclonal antibodies are directed against malignant B cells. In the case of T-ALL, some studies have been performed with alemtuzumab, since it recognises T cells as well as B cells, with results that are not very promising and considerable side effects.<a class="elsevierStyleCrossRef" href="#bib0490">38</a>Future treatmentsThe new treatments in T-ALL must be based on molecular data and on the subtype, that is, they must be as personalised as possible. In this sense, the molecular characterisation of ETP subtype of T-ALL, of poor prognosis in children as well as in adults, opens the possibility to use drugs used in the treatment of AML, such as FLT3 inhibitors<a class="elsevierStyleCrossRef" href="#bib0495">39</a> or JAK/STAT inhibitors.<a class="elsevierStyleCrossRef" href="#bib0500">40</a> Other future therapeutic strategies could be the methyltransferase inhibitors or the histone deacetylase inhibitors for the T-ALL in adults, as well as CDK–cyclin complex inhibitors: D3 CDK4/6, which are efficient in the inhibition of T blast proliferation, at diagnosis as well as at relapse in vivo.<a class="elsevierStyleCrossRef" href="#bib0505">41</a>One form of specific treatment is using as therapeutic target proteins that act downstream of the cellular receptor and have regulatory functions in the cellular signalling pathway affected in the leukemic cell. One example is the phosphates. In T-ALL, deletions of PTPN2 were identified in patients that also have deleted TLX1, and it has been observed that a decrease of the phosphatase expression in non-mutated blasts increases the proliferation and sensitivity to cytokines, on top of adversely affecting the response to inimatinib.<a class="elsevierStyleCrossRef" href="#bib0510">42</a> Another key phosphatase in the progression of T-ALL is the serine/threonine phosphatase PP2B or calcineurin. The inhibition of the phosphatase activity through the use of FK506 and ciclosporin implies a proliferation blockage and an increase of the apoptosis of the mouse leukemic cells.<a class="elsevierStyleCrossRef" href="#bib0515">43</a> Moreover, studies performed in a model of T cell-leukemia in the mouse, where the blasts do not express the phosphatase, have observed that calcineurin is key for tumour development since the absence of phosphatase prevents the leukemia-initiating cells from developing the type T.<a class="elsevierStyleCrossRef" href="#bib0520">44</a>ConclusionSurvival improvement and, ultimately, the progress towards the cure of patients with T-ALL depend on having detailed molecular information relevant for the clinical practice with the purpose of narrowing down the risk and the treatment. These are the basis for personalised medicine. The progress in the molecular knowledge of T-ALL increases very rapidly since the technological support this knowledge is based on is continuously evolving. Sequencing platforms will continue improving to enable the detection of variables very poorly represented and processing of a higher number of samples to reduce costs. Likewise, new techniques will be incorporated, such as single cell sequencing, that will help understand and identify resistant clones. Notwithstanding, the greatest challenge is to be able to translate all this information into every day clinical practice. To that end, it is necessary to perform studies with human samples and develop humanised animal models of T-ALL, such as xenotransplantation. This is not possible without the preservation of good quality samples of patients with T-ALL in collections or biobanks, where the samples are collected and stored following a strict handling protocol, and all the collection legal aspects are properly complied with. Moreover, the prognostic meaning of the different biomarkers in patients included in homogeneous treatment protocols must be continuously assessed, and cooperation should be established with other national and international groups for the purposes of comparing data. In the long run, it is necessary to identify resistant clones and develop specific treatments directed towards these minority cells located in specific niches, such as the bone marrow. These treatments must be capable of eliminating the resistant clone before the patient's relapse (preventive treatment).FundingStudy partly subsidised with the RD12/0036/0829 project of the Network for Cooperative Research in Cancer (Red Temática de Investigación Cooperativa en Cáncer, RTICC) at the Instituto de Salud Carlos III (ISCIII). Jordi Ribera is funded by the Spanish Society of Haematology and Haemotherapy (Sociedad Española de Hematología y Hemoterapia, SEHH). Eulàlia Genescà is funded by the ISCIII (agreement CA12/00468).Conflict of interestThe authors declare that there are no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres577889" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec594579" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres577890" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec594578" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Towards a molecular characterisation “a la carte”" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Variations in the number of gene copies in precursor T-acute lymphoblastic leukemia" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Arrays of expression" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Next-generation sequencing" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Adult and childhood precursor T-acute lymphoblastic leukemia" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "A new protagonist in precursor T-acute lymphoblastic leukemia: micro-ribonucleic acids" ] ] ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Clinical involvement: prognostic value of biomarkers" ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Minimal residual disease" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Relapse and clonal heterogeneity" ] 9 => array:3 [ "identificador" => "sec0055" "titulo" => "Treatment" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Standard treatment" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "New treatments" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Immunotherapy" ] 3 => array:2 [ "identificador" => "sec0075" "titulo" => "Future treatments" ] ] ] 10 => array:2 [ "identificador" => "sec0080" "titulo" => "Conclusion" ] 11 => array:2 [ "identificador" => "sec0085" "titulo" => "Funding" ] 12 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-10-16" "fechaAceptado" => "2014-01-23" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec594579" "palabras" => array:4 [ 0 => "Acute T-cell lymphoblastic leukemia" 1 => "Molecular markers" 2 => "Biology" 3 => "Treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec594578" "palabras" => array:4 [ 0 => "Leucemia aguda linfoblástica T" 1 => "Marcadores moleculares" 2 => "Biología" 3 => "Tratamiento" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Acute lymphoblastic leukemia (ALL) is the most common cancer in children and the main cause of morbidity among childhood blood disorders. There are 2 subtypes according to the affected lymphoid progenitor: B-ALL and T-ALL. The T-ALL is the less common and, although historically was associated with poor prognosis in both adults and children, at present, treatment outcomes do not differ significantly between the 2 types of ALL. The T-ALL subtype is the most complex and heterogeneous at the genetic level and currently the one with less new therapeutic alternatives available. This trend is changing thanks to the remarkable progress upon understanding its biology. This review summarises the most recent and important biological findings in T-ALL and their possible therapeutic implications." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La leucemia aguda linfoblástica (LAL) es la neoplasia más frecuente en niños y la principal causa de morbilidad entre las alteraciones hemáticas infantiles. Existen 2 subtipos, según el progenitor linfoide afectado: LAL-B y LAL-T. La LAL-T es menos frecuente e históricamente se asociaba a mal pronóstico tanto en adultos como en niños, aunque en la actualidad los resultados del tratamiento no difieren significativamente entre ambos tipos de LAL. La LAL-T es el subtipo más complejo y heterogéneo a nivel genético y el que menos alternativas terapéuticas nuevas presenta en el momento actual. Esta tendencia está cambiando merced a los progresos notables que se están efectuando en el conocimiento de su biología. En esta revisión se resumen los hallazgos biológicos más importantes en la LAL-T efectuados en los últimos años y sus posibles implicaciones terapéuticas." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Genescà E, Ribera J, Ribera J-M. Leucemia aguda linfoblástica de precursores T: de la biología a la clínica. Med Clin (Barc). 2015;144:223–229." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "a: adults; c: children." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Affected gene \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Chromosomal lesion \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HOXA-RCTß \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inv(7)(p15;q34); t(7;7)(p15;q34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HOXA(SET-NUP214) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">del9q34; inv(14)(q11.2q13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HOXA(MLL-ENL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(11;19)(q23;p13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HOXA(CALM-AF10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(10;11)(p13;q14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TLX1(HOX11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(10;14)(q24;q21); t(7;10)(q34;q24) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4–7 (c)/14 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TLX3(HOX11L2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(5;14)(q35;q32) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 (c)/13 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NKX2.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inv(14)(q13;q32.33); t(7;14)(q34;q13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NKX2.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(14;20)(q11;p11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TAL1-RCTα/δ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(1;14)(p32;q11); t(1;7)(p32;q34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">SIL-TAL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">del1p32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9–30 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TAL2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(7;9)(q34;q32) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">LYL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(7;19)(q34;p13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">OLIG2(BHLHB1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(14;21)(q11.2;q22) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">One case described \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">LMO1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(11;14)(p15;q11); t(7;11)(q34;p15) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">LMO2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(11;14)(p13;q11); t(7;11)(q34;p13); del11p13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6; 3(del) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">LMO3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(7;12)(q34;p12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">c-MYB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(6;7)(q23;q34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 (c)/7 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab943127.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main recurrent chromosomal lesions in T-cell acute lymphoblastic leukemia that define molecular subgroups." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "a: adults; c: children." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Affected gene \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genetic lesion \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NOTCH1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(7;9)(q34;q13); activating mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1; 60 (activating mutation) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FBXW7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8–30 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CDKN2A/2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">del(9q21); methylation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">70 (c)/15 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CCND2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(7;12)(q34;p12); t(12;14)(p13;q11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">RB1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">del(13q14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">del(6q) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 (c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CDKN1B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">del(12p13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">MYC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(8;14)(q24;q11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">WT1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 (c)/12 (a)/8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">LEF1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7–11 (c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ETV6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17 (c)/12 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BCL11B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 (c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">RUNX1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.4 (c)/18 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">GATA3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">PTEN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Point mutation; del(10q22) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NUP214-ABL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Episomal amplification 9q34 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">EML1-ABL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(9;14)(q34;q32) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ETV6-ABL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(9;12)(q34;p13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1(c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BCR-ABL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(9;22)(q34;q11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NRAS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Activating mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5–10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NF1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 (c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">JAK1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Activating mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4–18 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ETV6-JAK2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">t(9;12)(p24;p13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">JAK3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Activating mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5 (c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FLT3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Activating mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (c)/4 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">IL7R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Activating mutation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">EZH2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (c)/15 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">SUZ12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (c)/4 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">EED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10 (c) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">PHF6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inhibitory mutation; deletion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 (c)/38 (a) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab943126.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Other genes recurrently altered in T-cell acute lymphoblastic leukemia." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "ETP: early T-cell precursor; T-ALL: Precursor T-acute lymphoblastic leukemia; NA: not analysed; TCR: T cell receptor." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col">Biomarker \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Prognosis</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Children \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adults \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">T-ALL subtype</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ETP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0320">4</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425">25</a>/without impact<a class="elsevierStyleCrossRef" href="#bib0525">45</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cortical \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Mature \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Chromosomal alterations (translocations)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CALM-AFA10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0530">46</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0525">45</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TAL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0545">49</a>/without impact<a class="elsevierStyleCrossRef" href="#bib0550">50</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TLX1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0555">51</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0560">52</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TLX3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0535">47</a>/without impact<a class="elsevierStyleCrossRef" href="#bib0545">49</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0565">53</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BCR-ABL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0570">54</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Chromosomal alterations (deletions)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CDKN2A/2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0575">55</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0580">56</a>/favourable (homozygous deletions)<a class="elsevierStyleCrossRef" href="#bib0425">25</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BCL11B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favourable (homozygous deletions)<a class="elsevierStyleCrossRef" href="#bib0425">25</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">TP53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable (heterozygous deletions)<a class="elsevierStyleCrossRef" href="#bib0425">25</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Chromosomal alterations (amplifications)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NUP214-ABL1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable if associated with the TLX3 expression<a class="elsevierStyleCrossRef" href="#bib0550">50</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Chromosomal alterations (punctual mutations)</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NOTCH1/FBWX7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favourable<a class="elsevierStyleCrossRefs" href="#bib0390">18,19</a>/favourable in early response<a class="elsevierStyleCrossRef" href="#bib0405">21</a>/without impact<a class="elsevierStyleCrossRef" href="#bib0400">20</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favourable<a class="elsevierStyleCrossRefs" href="#bib0410">22,23,25</a>/without impact<a class="elsevierStyleCrossRef" href="#bib0420">24</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">DNMT3A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425">25</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">IDH1/2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425">25</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">WT1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Without impact<a class="elsevierStyleCrossRef" href="#bib0590">58</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable in standard-risk T-ALL subgroup of thymic origin<a class="elsevierStyleCrossRef" href="#bib0590">58</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">RUNX1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0585">57</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">TCR</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Absence of biallelic deletion in TCRG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0595">59</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425">25</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Immunomarkers</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CD13+ (myeloid marker) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425">25</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CD8+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0425">25</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">CD62L+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0425">25</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Minimal residual disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prognostic factor regardless of treatment response<a class="elsevierStyleCrossRefs" href="#bib0430">26,60</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prognostic factor regardless of treatment response<a 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Acute lymphoblastic leukemia of T progenitors: From biology to clinics

Leucemia aguda linfoblástica de precursores T: de la biología a la clínica

Eulàlia Genescàa,

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egenesca@carrerasresearch.org

Corresponding author.

, Jordi Riberaa, Josep-Maria Riberaa,b

a Grupo de Investigación en LAL, Instituto de Investigación contra la Leucemia Josep Carreras (IJC), Badalona, Barcelona, Spain

b Servicio de Hematología Clínica, Instituto Catalán de Oncología (ICO)-Hospital Germans Trias i Pujol (HGTP), Universidad Autónoma de Barcelona (UAB), Badalona, Barcelona, Spain

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in children and 35&#8211;45&#37; in adults &#40;<a href="http://www.seer.cancer.gov/statistics">www&#46;seer&#46;cancer&#46;gov&#47;statistics</a>&#41;&#46; Specifically&#44; the T-ALL corresponds to 15&#37; of childhood acute leukemias and 25&#37; of the adult ones&#46; The curve of incidence presents only one peak located in the child&#47;adult boundary and the survival does not differ from that of the precursors B-ALL&#46; This T subtype is characterised by presenting a greater heterogeneity and genetic complexity&#44; making it attractive for research&#44; despite being a rare ALL subtype&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The purpose of this study is to summarise the latest scientific advances in T-ALL&#44; at a basic level as well as at a clinical level&#44; and show where the research is headed in this ALL subtype and which are the key items to resolve at medium&#8211;long term with the purpose of improving the treatment and survival of patients with this disease&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Towards a molecular characterisation &#8220;a la carte&#8221;</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Variations in the number of gene copies in precursor T-acute lymphoblastic leukemia</span><p id="par0015" class="elsevierStylePara elsevierViewall">In these last years&#44; the studies based on the use of large-scale and high-resolution genomic techniques have been of vital importance for the comprehension of ALL&#44; and especially revealing in T-ALL&#46; Since in 2005 Irving et al&#46; demonstrated that through <span class="elsevierStyleItalic">arrays</span> of <span class="elsevierStyleItalic">single nucleotide polymorphisms</span> &#40;SNP&#41; <span class="elsevierStyleItalic">loss of heterozygosity</span> &#40;LOH&#41; could be successfully identified in ALL&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> there have been numerous studies that involved new genes in the development of T-ALL through screening of <span class="elsevierStyleItalic">copy number variations</span> &#40;CNV&#41; with SNP arrays or with comparative genomic hybridisation arrays&#46; Thus&#44; focal alterations of copy number that imply a <span class="elsevierStyleItalic">TAL1</span>&#44; <span class="elsevierStyleItalic">LMO2</span>&#44; <span class="elsevierStyleItalic">PTEN</span>&#44; <span class="elsevierStyleItalic">FBXW7</span> and <span class="elsevierStyleItalic">MYB</span> deregulation&#44; among others&#44; have been identified<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a> &#40;<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Arrays of expression</span><p id="par0020" class="elsevierStylePara elsevierViewall">From the comparative studies of the pattern of expression of human T-ALL samples and normal T cells at different stages of differentiation&#44; a consensus has been reached regarding 3 big T-ALL subtypes that group the different subtypes based on the chromosomal abnormalities present in the leukemic cell&#58; &#40;a&#41; <span class="elsevierStyleItalic">early T-cell precursor</span> &#40;ETP&#41;&#44; characterised by the absence of CD1a&#44; CD4 and CD8 immunomarkers and the presence of myeloid or pluripotent cell markers such as CD117&#44; CD34&#44; HLA-DR&#44; CD13&#44; CD33&#44; CD11b&#44; or CD65<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a>&#59; &#40;b&#41; cortical subtype&#44; characterised by the aberrant expression of the transcription factor family with a <span class="elsevierStyleItalic">homeobox</span> domain&#44; such as <span class="elsevierStyleItalic">TLX3</span>&#44; <span class="elsevierStyleItalic">NKX2&#46;1</span> and <span class="elsevierStyleItalic">NKX2&#46;2</span>&#44;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">5&#8211;7</span></a> and by the expression of the CD1&#44; CD4 and CD8 immunomarkers<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">5</span></a> and Pre-T1 or Pre-T2&#47;Pre-T3 &#40;E&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> and &#40;c&#41; mature subtype&#44; characterised by the expression of the <span class="elsevierStyleItalic">TAL oncogene</span>&#44;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">5&#8211;7</span></a> CD4&#44; CD8 and CD3 immunomarkers<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">5</span></a> and T cell receptor&#945;&#946;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> In <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; there is a summary of the main chromosomal alterations that characterise these 3 molecular subtypes&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Next-generation sequencing</span><p id="par0025" class="elsevierStylePara elsevierViewall">Another great advance in the knowledge of new genes that participate in the development of T-ALL was produced with the development of the new <span class="elsevierStyleItalic">next generation sequencing</span> &#40;NGS&#41; platforms&#46; This technique enables the detection of punctual mutations with very high sensitivity and LOH and CNV with very high resolution&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the main genes with recurring punctual mutations that affect T-ALL&#46; At the beginning of the year 2012&#44; the Mullighan group&#44; at the <span class="elsevierStyleItalic">St&#46; Jude Children&#39;s Research Hospital</span>&#44; published the first complete sequencing of the ALL genome performed in 12 samples of ETP type childhood T-ALL&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a> and they demonstrated that this ALL subtype presents activating somatic mutations in cytokines and genes that participate in the <span class="elsevierStyleItalic">RAS pathway</span>&#44; such as <span class="elsevierStyleItalic">NRAS</span>&#44; <span class="elsevierStyleItalic">KRAS</span>&#44; <span class="elsevierStyleItalic">FLT3</span>&#44; <span class="elsevierStyleItalic">IL7R</span>&#44; <span class="elsevierStyleItalic">JAK3</span>&#44; <span class="elsevierStyleItalic">JAK1</span>&#44; <span class="elsevierStyleItalic">SH2B3</span> and <span class="elsevierStyleItalic">BRAF</span>&#44; as well as genetic alterations that inactivate genes that participate in the haematopoietic development&#44; such as <span class="elsevierStyleItalic">GATA3</span>&#44; <span class="elsevierStyleItalic">ETV6</span>&#44; <span class="elsevierStyleItalic">RUNX1</span>&#44; <span class="elsevierStyleItalic">IKZF1</span> and <span class="elsevierStyleItalic">EP300</span>&#44; and histone-modifying genes &#40;<span class="elsevierStyleItalic">EZH2</span>&#44; <span class="elsevierStyleItalic">EED</span>&#44; <span class="elsevierStyleItalic">SUZ12</span>&#44; <span class="elsevierStyleItalic">SETD2</span> and <span class="elsevierStyleItalic">EP300</span>&#41;&#46; It is worth mentioning that the mutational spectrum identified in the ETP leukemia was similar to that of the poor-prognosis acute myeloid leukemias &#40;AML&#41;&#44; with affected genes that define the pluripotent character of the myeloid cell&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a> Recently&#44; another complete exome study in ETP leukemia samples in adults has identified mutations in the <span class="elsevierStyleItalic">DNMT3A</span> methyltransferase in 16&#37; of the patients &#40;10&#47;68&#41;&#44; a similar frequency to the one detected in AML&#46; Moreover&#44; mutations have been found in the <span class="elsevierStyleItalic">FAT1</span> &#40;25&#37;&#41; and <span class="elsevierStyleItalic">FAT2</span> cadherins &#40;20&#37;&#41;&#44; thus involving genes that participate in cell adhesion and in the interaction between stromal and leukemic cell&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> Using this same technique&#44; De Keersmaecker et al&#46; identified mutations in the <span class="elsevierStyleItalic">CNOT3</span> gene in 3&#46;8&#37; &#40;8&#47;211&#41; of the T-ALL samples analysed&#46; The mutations identified cause a lower gene expression&#44; which evidences that <span class="elsevierStyleItalic">CNOT3</span> could act as a tumour suppressor gene&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> Moreover&#44; mutations were identified in the <span class="elsevierStyleItalic">RPL10</span> gene &#40;5&#46;2&#37;&#44; 11&#47;211&#41; and in the <span class="elsevierStyleItalic">RPL5</span> gene &#40;1&#46;9&#37;&#44; 4&#47;211&#41;&#46; Both genes codify by ribosomal proteins that are part of the 60S ribosomal complex&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> The recurring mutation most frequently observed in <span class="elsevierStyleItalic">RPL10</span>&#44; a change of Arg98Ser amino acid&#44; causes an increase of the proliferation and a defect in the ribosome biogenesis in lymphoid cells&#44; which demonstrates that this mutation could help the leukemic cell decrease its translational and growth activity in favour of proliferation&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Adult and childhood precursor T-acute lymphoblastic leukemia</span><p id="par0030" class="elsevierStylePara elsevierViewall">As the amount of genes involved in the T-ALL increases&#44; and also does the number of samples analysed&#44; adult and childhood T-ALLs are outlined as 2 differentiated subgroups&#46; The wide sequencing study performed by the Cools group in 67 T-ALL samples at the time of diagnosis observed that the number of mutations in adults was 2&#46;5 times higher than in children &#40;21&#46;0 versus 8&#46;2&#41;&#44; with a clear correlation between age and number of mutations&#46; However&#44; this fact did not imply any prognostic significance&#46; Likewise&#44; it was observed that adults presented mostly mutations in genes regulatory of the methylation pattern&#44; such as <span class="elsevierStyleItalic">KDM6A</span> &#40;4&#46;5&#37;&#44; 3&#47;67&#41; and <span class="elsevierStyleItalic">MAGEC3</span> &#40;3&#46;0&#37;&#44; 2&#47;67&#41;&#44; in transcriptional regulators&#44; such as <span class="elsevierStyleItalic">PHF6</span> &#40;17&#46;9&#37;&#44; 12&#47;67&#41;&#44; and in tumour suppressor genes&#44; such as <span class="elsevierStyleItalic">CNOT3</span> and <span class="elsevierStyleItalic">FBXW7</span> &#40;11&#46;9&#37;&#44; 8&#47;67&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> Likewise&#44; in the exome study performed by Neumann et al&#46; in samples of adults with ETP T-ALL&#44; specific mutations in methylation regulatory genes were also identified&#44; such as <span class="elsevierStyleItalic">DNMT3A methyltransferase</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> In other respects&#44; as stated before&#44; in the exome study performed by De Keersmaecker et al&#46;&#44; specific mutations in proteins that are part of the 60S ribosomal complex were identified in samples of childhood ALL&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> All these data would evidence that the T-ALL pathogenesis in adults and children could be different&#46; While in adults the epigenetic factors would have a determining role&#44; in children the changes in the cellular metabolism and in the biosynthesis of organelles and macromolecules necessary for the generation of new cells would develop a key role in the tumour development&#46; This is a new exploration field in T-ALL that we will see developing in the immediate future&#44; with consequences at therapeutic level&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">A new protagonist in precursor T-acute lymphoblastic leukemia&#58; micro-ribonucleic acids</span><p id="par0035" class="elsevierStylePara elsevierViewall">With the advance in the molecular knowledge of T-ALL&#44; not only the identification of tumour suppressor genes and oncogenes was possible&#44; but also the identification of mutations in non-codifying genes&#44; such as micro-ribonucleic acids &#40;miRNA&#41;&#46; miRNAs are one of the most abundant regulatory molecules in multicellular organisms and they affect the expression of a great number of genes&#46; The miR-17-92 <span class="elsevierStyleItalic">cluster</span>&#44; and specifically the miR-19b&#44; was the first described miRNA that was overexpressed in human samples of T-ALL&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> Subsequently&#44; the existence of a double clonal translocation of TCR&#47;D locus in the chromosomal band 14q11 was described&#46; This affected&#44; on the one hand&#44; <span class="elsevierStyleItalic">NOTCH1</span>&#44; through the t&#40;9&#59;14&#41;&#40;q34&#59;q11&#41; translocation&#44; and on the other hand&#44; the miR-17-92 <span class="elsevierStyleItalic">cluster</span>&#44; through t&#40;13&#59;14&#41;&#40;q32&#59;q11&#41;&#46; Shortly afterwards&#44; it was observed that the coexpression of the active form of <span class="elsevierStyleItalic">NOTCH1</span> and miR-19 in the mouse haematopoietic progenitors accelerated the <span class="elsevierStyleItalic">NOTCH1</span>-induced leukemia in the murine model&#44; demonstrating the cooperation of this miRNA in T-ALL development&#46; Moreover&#44; the <span class="elsevierStyleItalic">BIM</span>&#44; <span class="elsevierStyleItalic">PTEN</span>&#44; <span class="elsevierStyleItalic">PRKAA1</span>&#44; <span class="elsevierStyleItalic">DOCK5</span> and <span class="elsevierStyleItalic">PPP2R5E</span> genes were identified as genes regulated by such miRNA&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">12</span></a> In 2011&#44; the first miRNA screening in T-ALL was published&#46; Mavrakis et al&#46; identified 5 miRNA &#40;miR-19b&#44; miR-20a&#44; miR-26a&#44; miR-92 and miR-223&#41; capable of accelerating leukemia in a mouse T-ALL model&#44; and they also observed that these miRNAs act cooperatively inhibiting tumour suppressor genes&#44; such as <span class="elsevierStyleItalic">PTEN</span>&#44; <span class="elsevierStyleItalic">BIM</span> and <span class="elsevierStyleItalic">FBXW7</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></a> The Baldus group&#44; specialised in the molecular characterisation of ETP T-ALLs&#44; observed the miR-221 and miR-222 overexpression&#44; and the miR-151-3p&#44; miR-19a&#44; miR-20b&#44; miR-342-3p&#44; miR-363 and miR-576-3p underexpression through the analysis of miRNA expression arrays in samples of adults with ETP T-ALL&#46; The aforementioned group also demonstrated that the miR-222 overexpression implied a decrease of the values of the <span class="elsevierStyleItalic">ETS1</span> gene messenger RNA&#44; which regulates the differentiation of macrophages&#44; evidencing that the miR-222 overexpression in the ETP T-ALLs would imprint the myeloid character present in this subtype&#46; Moreover&#44; the group observed that the high expression of miRNA was positively associated with the expression of genes with prognostic impact in the ETP T-ALL&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a> It has recently been described that the miR-150 expression&#44; a miRNA that has been widely studied in B cells&#44; increases in CD4<span class="elsevierStyleSup">&#43;</span> or CD8<span class="elsevierStyleSup">&#43;</span> T cells and decreases in CD4<span class="elsevierStyleSup">&#43;</span>&#8211;CD8<span class="elsevierStyleSup">&#43;</span> T cells &#40;double-positive T cells&#44; T-DP&#41;&#44; and it is capable of regulating the <span class="elsevierStyleItalic">NOTCH3</span> expression in T-DPs as well as in CD4<span class="elsevierStyleSup">&#43;</span> or CD8<span class="elsevierStyleSup">&#43;</span> T cells&#46; Moreover&#44; authors indicate a possible role of this miRNA in T-ALL since it regulates the proliferation and the apoptosis of T-cells cell lines&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> In the mature subtype T-ALLs&#44; that overexpress <span class="elsevierStyleItalic">TAL1</span>&#44; it has been observed that the <span class="elsevierStyleItalic">TAL1</span> oncogene expression causes a miR-223 overexpression and&#44; in consequence&#44; a deregulation of miRNA targets such as <span class="elsevierStyleItalic">FBXW7</span>&#44; key tumour suppressor in the development of T-ALL&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">16</span></a> Undoubtedly&#44; this type of regulation will be described in other types of cancer&#46; Finally&#44; miR-142-3p&#44; which is overexpressed in T-cell leukemias&#44;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">13&#44;17</span></a> has been related to a possible mechanism of glucocorticosteroid resistance&#44; since it is capable of regulating the translation of the &#945; glucocorticosteroid receptor isoform &#40;GR&#945;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a></p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Clinical involvement&#58; prognostic value of biomarkers</span><p id="par0040" class="elsevierStylePara elsevierViewall">The method to assess if the information obtained in the basic investigation is clinically relevant is by correlating the data with the medical information from groups of patients included in homogeneous treatment protocols&#44; and establishing the prognostic value of the different molecular markers&#46; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> summarises the molecular markers with prognostic values identified up to date&#46; We can observe that although the number of markers with prognostic significance increases&#44; the studies that obtain different&#44; sometimes conflicting results also increase&#46; The clearest example is the predictive value of the mutations in <span class="elsevierStyleItalic">NOTCH1</span>&#47;<span class="elsevierStyleItalic">FBWX7</span> in children&#46; Two different groups&#44; with 2 different treatment protocols &#40;the English MRC UKALL-2003<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">18</span></a> and the German ALL-BFM 2000<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a>&#41; have confirmed the mutations in <span class="elsevierStyleItalic">NOTCH1</span> as favourable prognosis marker in childhood T-ALL&#46; Notwithstanding&#44; the American <span class="elsevierStyleItalic">Pediatric Oncology Group</span> did not find predictive value in a study of 47 patients included in 5 different treatment protocols&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a> Likewise&#44; the multicentre study performed by a French group&#44; which included children treated with 2 different protocols &#40;EORTC 5881&#47;58951&#41;&#44; observed that the <span class="elsevierStyleItalic">NOTCH1</span> mutations only had favourable prognosis value in the early response to the treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> In the case of adults&#44; the prognosis value of <span class="elsevierStyleItalic">NOTCH1</span>&#47;<span class="elsevierStyleItalic">FBWX7</span> is even more difficult to analyse because there are less studies and because there are contradicting results based on the different treatment protocols &#40;LALA-94 and GRAALL03&#47;05&#44; from the French group&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">22&#44;23</span></a> and protocols GMALL 05&#47;93 and 06&#47;99 from the German group<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a>&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Recently&#44; a study performed with patients included in one protocol from the <span class="elsevierStyleItalic">Eastern Cooperative Oncology Group</span> &#40;E2993ECOG&#41; has confirmed the favourable prognosis value of the mutations in <span class="elsevierStyleItalic">NOTCH1</span>&#47;<span class="elsevierStyleItalic">FBWX7</span> in a series of 53 adult patients&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a> Finally&#44; on the one hand&#44; there is a variation of results associated with the use of samples coming from different treatment protocols within the same study&#44; and&#44; on the other hand&#44; a different impact based on the application of different treatment protocols among the different work teams in T-ALL&#46; Therefore&#44; it is necessary to perform international cooperation studies that include different work teams with their respective treatment protocol to be able to clearly define the clinical involvement of the different molecular markers currently available&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Minimal residual disease</span><p id="par0045" class="elsevierStylePara elsevierViewall">The analysis of the minimal residual disease &#40;MRD&#41;&#44; either via flow cytometry &#40;for aberrant immunophenotypes&#41;&#44; via detection of the polymerase chain reaction of fusion gene &#40;for leukemias with <span class="elsevierStyleItalic">T cell receptor</span> &#91;TCR&#93; translocation or others&#41;&#44; or TCR rearrangement&#44; is the clearest and most potent existing prognostic factor of treatment response in T-ALL&#44; both in children as well as in adults&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">26&#44;27</span></a> This marker is very useful to follow-up on the patient&#39;s response to treatment and for the early detection of groups with high risk of relapse&#44; with the possibility of adapting&#44; and even anticipating&#44; treatment in these patients&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Relapse and clonal heterogeneity</span><p id="par0050" class="elsevierStylePara elsevierViewall">The approaches at genomic scale have also helped design the clonal heterogeneity in T-ALL at the time of diagnosis&#46; The importance of this subclonal heterogeneity has been recently manifested via the comparative analysis of the CNV of samples of childhood T-ALL at diagnosis and relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a> Clappier et al&#46; observed that even though leukemic cells at diagnosis and relapse share a great number of genetic lesions&#44; at relapse&#44; there are genetic mutations and&#47;or alterations that are underrepresented in diagnosis samples&#46; Thus&#44; at the time of diagnosis&#44; the leukemia would be composed of different subclones that would share the same preleukemic common ancestor&#44; but only one or a few would be capable of acquiring a selective advantage in a determined microenvironment &#40;niche&#41; and proliferate until developing the leukemia&#46; The relapse would mainly be composed of clones underrepresented in diagnosis&#44; which have been selected during treatment&#46; The mutational screening of pairs of samples of patients with childhood ALL at diagnosis and relapse via NGS identified that the <span class="elsevierStyleItalic">NT5C2</span> gene was specifically mutated at relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> Gene sequencing in a greater number of patients confirmed that the mutations in <span class="elsevierStyleItalic">NT5C2</span> were found in 19&#37; of the samples of T-ALL in relapse&#46; These mutations create resistance to 6-mercaptopurine and 6-thioguanine&#44; 2 analogues of nucleoside used in the treatment of T-ALL&#44; which demonstrated for the first time that the leukemia developed in relapse is resistant to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> A similar study published by Meyer et al&#46; was capable of detecting mutations in <span class="elsevierStyleItalic">NT5C2</span> at diagnosis in 2&#47;7 samples analysed&#44; with a frequency of mutated alleles of 0&#46;01&#37; and 0&#46;02&#37;&#44; respectively&#44; which indicates that in some cases the clone resistant to treatment already exists at diagnosis at a very low frequency&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a> These data evidence that the treatment at diagnosis and relapse should be different&#46; Notwithstanding&#44; they do not enable the prediction or anticipation of the resistant clones before starting treatment&#46; Besides&#44; they question the origin of the clone resistant to treatment in those cases in which it is not detected at diagnosis&#46; Maybe the generation of subclones would be a much more dynamic process clearly influenced by the selective pressures of the microenvironment&#44; such as treatment&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Treatment</span><p id="par0055" class="elsevierStylePara elsevierViewall">Many of the drugs used in the treatment of ALL were developed before the 1970s&#46; Since then&#44; the treatment of ALL has not ceased to improve until achieving a survival rate close to 90&#37; in childhood ALL&#44; and in adults&#44; between 30&#37; and 40&#37;&#46; This has happened due to the numerous treatment protocols developed by different work teams in ALL&#44; in which the use of different drug combinations&#44; their doses and sequences of administration have been optimised&#46; Added to this&#44; it is worth mentioning the ability to monitor treatment response through MRD detection and to adapt the treatment based on the response&#46; Moreover&#44; the identification of specific risk groups based on the ALL molecular characteristics&#44; such as the Philadelphia chromosome ALLs&#44; has enabled the administration of more specific and efficient treatments&#46; However&#44; using treatment strategies alike in children and adults&#44; the cure rate in the latter is still low&#46; This is due to the fact that the disease is genetically more heterogeneous and complex&#44; with a greater presence of genetic variables of bad prognosis&#44; and because&#44; in many cases&#44; the adult does not tolerate the treatment intensity and density administered to children&#46;</p><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Standard treatment</span><p id="par0060" class="elsevierStylePara elsevierViewall">Patients with T-ALL&#44; except for the adults with cortical subtype and less than 100<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span> leukocytes&#47;L in blood at the time of diagnosis&#44; are included in the high-risk protocols&#44; that are generally the same as or very similar to those of the precursor B-ALL&#44; which is noteworthy since they are diseases that are different at genetic level&#46; Notwithstanding&#44; there are differences between treatment protocols among adults and children&#44; since the therapeutic regime in the latter is more intensive&#44; using a higher frequency of cycles and higher cytostatic concentrations&#46; In young adults&#44; there is a tendency to apply paediatric protocols and this has implied an improvement in global survival&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> However&#44; the application of these therapeutic regimes is only feasible in patients with a maximum age of 45&#8211;55 years&#44; since if they are applied in older patients&#44; the increase of treatment-related mortality neutralises the positive effect of the treatment itself&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> In general&#44; adult patients with T-ALL and high-risk criteria are treated with chemotherapy followed by allogeneic haematopoietic progenitor cell transplantation&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">New treatments</span><p id="par0065" class="elsevierStylePara elsevierViewall">Some of the molecular alterations identified in ALL have been used as targets of new specific drugs&#46; The most paradigmatic example is the <span class="elsevierStyleItalic">BCR-ABL1</span> fusion gene and the development of tyrosine-kinase inhibitors &#40;imatinib&#44; dasatinib&#44; nilotinib&#44; bosutinib and ponatinib&#44; among others&#41;&#44; some of which have been successfully assayed in children and adults with ALL with the aforementioned translocation&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">32&#44;33</span></a> A minority of the patients with T-ALL presents genetic alterations that affect the <span class="elsevierStyleItalic">ABL1</span> gene&#44; such as <span class="elsevierStyleItalic">NUP214-ABL1</span>&#44; <span class="elsevierStyleItalic">EML1-ABL1</span> and <span class="elsevierStyleItalic">ETV6-ABL1</span>&#44; for which the efficiency of these inhibitors is also being investigated&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">One of the drugs approved for the treatment of resistant T-ALL or T-ALL in second or subsequent relapse is nelarabine&#46; This analogue of deoxyguanosine&#44; which is specifically accumulated in T cells&#44; has offered promising results in phase I and II studies performed in adults as well as in children in relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> The neurological toxicity is the most relevant toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> The <span class="elsevierStyleItalic">Children&#39;s Oncology Group</span> demonstrated that the inclusion of nelarabine in the intensive treatment with chemotherapy in high-risk patients diagnosed with de novo T-ALL was feasible&#44; with promising results&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a> The Group has included this combination in its current treatment protocol &#40;COG AALL0434&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Immunotherapy</span><p id="par0075" class="elsevierStylePara elsevierViewall">A great step forward in the treatment of ALL has been the incorporation of specific therapy via monoclonal antibodies&#44; such as anti-CD20 &#40;rituximab&#41;&#44; anti-CD19 &#40;blinatumomab&#44; which is also anti-CD3&#41;&#44; anti-CD52 &#40;alemtuzumab&#41;&#44; anti-CD22 &#40;epratuzumab and inotuzumab ozogamicin&#41; and anti-CD33 &#40;gemtuzumab ozogamicin&#41;&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a> Most of these monoclonal antibodies are directed against malignant B cells&#46; In the case of T-ALL&#44; some studies have been performed with alemtuzumab&#44; since it recognises T cells as well as B cells&#44; with results that are not very promising and considerable side effects&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Future treatments</span><p id="par0080" class="elsevierStylePara elsevierViewall">The new treatments in T-ALL must be based on molecular data and on the subtype&#44; that is&#44; they must be as personalised as possible&#46; In this sense&#44; the molecular characterisation of ETP subtype of T-ALL&#44; of poor prognosis in children as well as in adults&#44; opens the possibility to use drugs used in the treatment of AML&#44; such as FLT3 inhibitors<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a> or JAK&#47;STAT inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a> Other future therapeutic strategies could be the methyltransferase inhibitors or the histone deacetylase inhibitors for the T-ALL in adults&#44; as well as CDK&#8211;cyclin complex inhibitors&#58; D3 CDK4&#47;6&#44; which are efficient in the inhibition of T blast proliferation&#44; at diagnosis as well as at relapse in vivo&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">One form of specific treatment is using as therapeutic target proteins that act <span class="elsevierStyleItalic">downstream</span> of the cellular receptor and have regulatory functions in the cellular signalling pathway affected in the leukemic cell&#46; One example is the phosphates&#46; In T-ALL&#44; deletions of <span class="elsevierStyleItalic">PTPN2</span> were identified in patients that also have deleted <span class="elsevierStyleItalic">TLX1</span>&#44; and it has been observed that a decrease of the phosphatase expression in non-mutated blasts increases the proliferation and sensitivity to cytokines&#44; on top of adversely affecting the response to inimatinib&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">42</span></a> Another key phosphatase in the progression of T-ALL is the serine&#47;threonine phosphatase PP2B or calcineurin&#46; The inhibition of the phosphatase activity through the use of FK506 and ciclosporin implies a proliferation blockage and an increase of the apoptosis of the mouse leukemic cells&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">43</span></a> Moreover&#44; studies performed in a model of T cell-leukemia in the mouse&#44; where the blasts do not express the phosphatase&#44; have observed that calcineurin is key for tumour development since the absence of phosphatase prevents the leukemia-initiating cells from developing the type T&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">44</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Survival improvement and&#44; ultimately&#44; the progress towards the cure of patients with T-ALL depend on having detailed molecular information relevant for the clinical practice with the purpose of narrowing down the risk and the treatment&#46; These are the basis for personalised medicine&#46; The progress in the molecular knowledge of T-ALL increases very rapidly since the technological support this knowledge is based on is continuously evolving&#46; Sequencing platforms will continue improving to enable the detection of variables very poorly represented and processing of a higher number of samples to reduce costs&#46; Likewise&#44; new techniques will be incorporated&#44; such as <span class="elsevierStyleItalic">single cell sequencing</span>&#44; that will help understand and identify resistant clones&#46; Notwithstanding&#44; the greatest challenge is to be able to translate all this information into every day clinical practice&#46; To that end&#44; it is necessary to perform studies with human samples and develop humanised animal models of T-ALL&#44; such as xenotransplantation&#46; This is not possible without the preservation of good quality samples of patients with T-ALL in collections or biobanks&#44; where the samples are collected and stored following a strict handling protocol&#44; and all the collection legal aspects are properly complied with&#46; Moreover&#44; the prognostic meaning of the different biomarkers in patients included in homogeneous treatment protocols must be continuously assessed&#44; and cooperation should be established with other national and international groups for the purposes of comparing data&#46; In the long run&#44; it is necessary to identify resistant clones and develop specific treatments directed towards these minority cells located in specific niches&#44; such as the bone marrow&#46; These treatments must be capable of eliminating the resistant clone before the patient&#39;s relapse &#40;preventive treatment&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Funding</span><p id="par0095" class="elsevierStylePara elsevierViewall">Study partly subsidised with the RD12&#47;0036&#47;0829 project of the Network for Cooperative Research in Cancer &#40;Red Tem&#225;tica de Investigaci&#243;n Cooperativa en C&#225;ncer&#44; RTICC&#41; at the Instituto de Salud Carlos III &#40;ISCIII&#41;&#46; Jordi Ribera is funded by the <span class="elsevierStyleGrantSponsor" id="gs1">Spanish Society of Haematology and Haemotherapy</span> &#40;Sociedad Espa&#241;ola de Hematolog&#237;a y Hemoterapia&#44; SEHH&#41;&#46; Eul&#224;lia Genesc&#224; is funded by the <span class="elsevierStyleGrantSponsor" id="gs2">ISCIII</span> &#40;agreement <span class="elsevierStyleGrantNumber" refid="gs2">CA12&#47;00468</span>&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors declare that there are no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres577889"
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              "identificador" => "abst0005"
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        1 => array:2 [
          "identificador" => "xpalclavsec594579"
          "titulo" => "Keywords"
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          "titulo" => "Resumen"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Towards a molecular characterisation &#8220;a la carte&#8221;"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Variations in the number of gene copies in precursor T-acute lymphoblastic leukemia"
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              "identificador" => "sec0020"
              "titulo" => "Arrays of expression"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Next-generation sequencing"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Adult and childhood precursor T-acute lymphoblastic leukemia"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "A new protagonist in precursor T-acute lymphoblastic leukemia&#58; micro-ribonucleic acids"
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          ]
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          "identificador" => "sec0040"
          "titulo" => "Clinical involvement&#58; prognostic value of biomarkers"
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        7 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Minimal residual disease"
        ]
        8 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Relapse and clonal heterogeneity"
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          "identificador" => "sec0055"
          "titulo" => "Treatment"
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              "identificador" => "sec0060"
              "titulo" => "Standard treatment"
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            1 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "New treatments"
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              "identificador" => "sec0070"
              "titulo" => "Immunotherapy"
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              "identificador" => "sec0075"
              "titulo" => "Future treatments"
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          "titulo" => "Conclusion"
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          "titulo" => "Funding"
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          "identificador" => "sec0090"
          "titulo" => "Conflict of interest"
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        13 => array:1 [
          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-10-16"
    "fechaAceptado" => "2014-01-23"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec594579"
          "palabras" => array:4 [
            0 => "Acute T-cell lymphoblastic leukemia"
            1 => "Molecular markers"
            2 => "Biology"
            3 => "Treatment"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec594578"
          "palabras" => array:4 [
            0 => "Leucemia aguda linfobl&#225;stica T"
            1 => "Marcadores moleculares"
            2 => "Biolog&#237;a"
            3 => "Tratamiento"
          ]
        ]
      ]
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Acute lymphoblastic leukemia &#40;ALL&#41; is the most common cancer in children and the main cause of morbidity among childhood blood disorders&#46; There are 2 subtypes according to the affected lymphoid progenitor&#58; B-ALL and T-ALL&#46; The T-ALL is the less common and&#44; although historically was associated with poor prognosis in both adults and children&#44; at present&#44; treatment outcomes do not differ significantly between the 2 types of ALL&#46; The T-ALL subtype is the most complex and heterogeneous at the genetic level and currently the one with less new therapeutic alternatives available&#46; This trend is changing thanks to the remarkable progress upon understanding its biology&#46; This review summarises the most recent and important biological findings in T-ALL and their possible therapeutic implications&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La leucemia aguda linfobl&#225;stica &#40;LAL&#41; es la neoplasia m&#225;s frecuente en ni&#241;os y la principal causa de morbilidad entre las alteraciones hem&#225;ticas infantiles&#46; Existen 2 subtipos&#44; seg&#250;n el progenitor linfoide afectado&#58; LAL-B y LAL-T&#46; La LAL-T es menos frecuente e hist&#243;ricamente se asociaba a mal pron&#243;stico tanto en adultos como en ni&#241;os&#44; aunque en la actualidad los resultados del tratamiento no difieren significativamente entre ambos tipos de LAL&#46; La LAL-T es el subtipo m&#225;s complejo y heterog&#233;neo a nivel gen&#233;tico y el que menos alternativas terap&#233;uticas nuevas presenta en el momento actual&#46; Esta tendencia est&#225; cambiando merced a los progresos notables que se est&#225;n efectuando en el conocimiento de su biolog&#237;a&#46; En esta revisi&#243;n se resumen los hallazgos biol&#243;gicos m&#225;s importantes en la LAL-T efectuados en los &#250;ltimos a&#241;os y sus posibles implicaciones terap&#233;uticas&#46;</p></span>"
      ]
    ]
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Genesc&#224; E&#44; Ribera J&#44; Ribera J-M&#46; Leucemia aguda linfobl&#225;stica de precursores T&#58; de la biolog&#237;a a la cl&#237;nica&#46; Med Clin &#40;Barc&#41;&#46; 2015&#59;144&#58;223&#8211;229&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Affected gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Chromosomal lesion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">HOXA-RCT&#223;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inv&#40;7&#41;&#40;p15&#59;q34&#41;&#59; t&#40;7&#59;7&#41;&#40;p15&#59;q34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">HOXA&#40;SET-NUP214&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">del9q34&#59; inv&#40;14&#41;&#40;q11&#46;2q13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">HOXA&#40;MLL-ENL&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;11&#59;19&#41;&#40;q23&#59;p13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">HOXA&#40;CALM-AF10&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;10&#59;11&#41;&#40;p13&#59;q14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">TLX1&#40;HOX11&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;10&#59;14&#41;&#40;q24&#59;q21&#41;&#59; t&#40;7&#59;10&#41;&#40;q34&#59;q24&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#8211;7 &#40;c&#41;&#47;14 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">TLX3&#40;HOX11L2&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;5&#59;14&#41;&#40;q35&#59;q32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;c&#41;&#47;13 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">NKX2&#46;1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inv&#40;14&#41;&#40;q13&#59;q32&#46;33&#41;&#59; t&#40;7&#59;14&#41;&#40;q34&#59;q13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">NKX2&#46;2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;14&#59;20&#41;&#40;q11&#59;p11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">TAL1-RCT&#945;&#47;&#948;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;1&#59;14&#41;&#40;p32&#59;q11&#41;&#59; t&#40;1&#59;7&#41;&#40;p32&#59;q34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">SIL-TAL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">del1p32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#8211;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">TAL2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;7&#59;9&#41;&#40;q34&#59;q32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">LYL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;7&#59;19&#41;&#40;q34&#59;p13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">OLIG2&#40;BHLHB1&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;14&#59;21&#41;&#40;q11&#46;2&#59;q22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">One case described&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">LMO1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;11&#59;14&#41;&#40;p15&#59;q11&#41;&#59; t&#40;7&#59;11&#41;&#40;q34&#59;p15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">LMO2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;11&#59;14&#41;&#40;p13&#59;q11&#41;&#59; t&#40;7&#59;11&#41;&#40;q34&#59;p13&#41;&#59; del11p13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#59; 3&#40;del&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">LMO3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;7&#59;12&#41;&#40;q34&#59;p12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">c-MYB</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;6&#59;7&#41;&#40;q23&#59;q34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;c&#41;&#47;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Main recurrent chromosomal lesions in T-cell acute lymphoblastic leukemia that define molecular subgroups&#46;</p>"
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        "etiqueta" => "Table 2"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">a&#58; adults&#59; c&#58; children&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Affected gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genetic lesion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">NOTCH1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;7&#59;9&#41;&#40;q34&#59;q13&#41;&#59; activating mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#59; 60 &#40;activating mutation&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">FBXW7</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#8211;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">CDKN2A&#47;2B</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">del&#40;9q21&#41;&#59; methylation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70 &#40;c&#41;&#47;15 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">CCND2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;7&#59;12&#41;&#40;q34&#59;p12&#41;&#59; t&#40;12&#59;14&#41;&#40;p13&#59;q11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">RB1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">del&#40;13q14&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">del&#40;6q&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18 &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">CDKN1B</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">del&#40;12p13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">MYC</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;8&#59;14&#41;&#40;q24&#59;q11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">WT1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;c&#41;&#47;12 &#40;a&#41;&#47;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">LEF1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#8211;11 &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">ETV6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17 &#40;c&#41;&#47;12 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BCL11B</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">RUNX1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;4 &#40;c&#41;&#47;18 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">GATA3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">PTEN</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Point mutation&#59; del&#40;10q22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">NUP214-ABL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Episomal amplification 9q34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">EML1-ABL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;9&#59;14&#41;&#40;q34&#59;q32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">ETV6-ABL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;9&#59;12&#41;&#40;q34&#59;p13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1&#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BCR-ABL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;9&#59;22&#41;&#40;q34&#59;q11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">NRAS</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Activating mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8211;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">NF1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">JAK1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Activating mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#8211;18 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">ETV6-JAK2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">t&#40;9&#59;12&#41;&#40;p24&#59;p13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;1 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">JAK3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Activating mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">FLT3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Activating mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;c&#41;&#47;4 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">IL7R</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Activating mutation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">EZH2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;c&#41;&#47;15 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">SUZ12</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;c&#41;&#47;4 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">EED</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">PHF6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inhibitory mutation&#59; deletion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16 &#40;c&#41;&#47;38 &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Other genes recurrently altered in T-cell acute lymphoblastic leukemia&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">ETP&#58; early T-cell precursor&#59; T-ALL&#58; Precursor T-acute lymphoblastic leukemia&#59; NA&#58; not analysed&#59; TCR&#58; T cell receptor&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col">Biomarker&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Prognosis</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Children&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adults&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">T-ALL subtype</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>ETP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&#47;without impact<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">45</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cortical&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mature&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Chromosomal alterations &#40;translocations&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CALM-AFA10</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">45</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">TAL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a>&#47;without impact<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">TLX1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">TLX3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a>&#47;without impact<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">53</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">BCR-ABL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Chromosomal alterations &#40;deletions&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CDKN2A&#47;2B</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a>&#47;favourable &#40;homozygous deletions&#41;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">BCL11B</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favourable &#40;homozygous deletions&#41;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">TP53</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable &#40;heterozygous deletions&#41;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Chromosomal alterations &#40;amplifications&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">NUP214-ABL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable if associated with the <span class="elsevierStyleItalic">TLX3 expression</span><a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Chromosomal alterations &#40;punctual mutations&#41;</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">NOTCH1&#47;FBWX7</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favourable<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">18&#44;19</span></a>&#47;favourable in early response<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a>&#47;without impact<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favourable<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">22&#44;23&#44;25</span></a>&#47;without impact<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">DNMT3A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">IDH1&#47;2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">WT1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Without impact<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable in standard-risk T-ALL subgroup of thymic origin<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">RUNX1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">TCR</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Absence of biallelic deletion in <span class="elsevierStyleItalic">TCRG</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Immunomarkers</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CD13<span class="elsevierStyleSup">&#43;</span> &#40;myeloid marker&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unfavourable<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CD8<span class="elsevierStyleSup">&#43;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CD62L<span class="elsevierStyleSup">&#43;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favourable<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Minimal residual disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prognostic factor regardless of treatment response<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">26&#44;60</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prognostic factor regardless of treatment response<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">27&#44;48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Main prognosis-indicating biomarkers in the T-cell acute lymphoblastic leukemia&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:60 [
            0 => array:3 [
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                          "etal" => false
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                            1 => "M&#46; Schrappe"
                            2 => "R&#46;C&#46; Ribeiro"
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            1 => array:3 [
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              "referencia" => array:1 [
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                            0 => "J&#46;A&#46; Irving"
                            1 => "L&#46; Bloodworth"
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                            3 => "M&#46;C&#46; Case"
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            2 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
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                            0 => "C&#46;G&#46; Mullighan"
                            1 => "J&#46;R&#46; Downing"
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                  "host" => array:1 [
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                      "Revista" => array:7 [
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                        "itemHostRev" => array:3 [
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            3 => array:3 [
              "identificador" => "bib0320"
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                      "titulo" => "Early T-cell precursor leukaemia&#58; a subtype of very high-risk acute lymphoblastic leukaemia"
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                        0 => array:2 [
                          "etal" => true
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                            0 => "E&#46; Coustan-Smith"
                            1 => "C&#46;G&#46; Mullighan"
                            2 => "M&#46; Onciu"
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            4 => array:3 [
              "identificador" => "bib0325"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia"
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                        0 => array:2 [
                          "etal" => true
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                            0 => "A&#46;A&#46; Ferrando"
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                            2 => "J&#46; Staunton"
                            3 => "M&#46;L&#46; Loh"
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                          ]
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Cell"
                        "fecha" => "2002"
                        "volumen" => "1"
                        "paginaInicial" => "75"
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            5 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "6"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia &#40;T-ALL&#41;"
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                          "etal" => true
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                            0 => "J&#46; Soulier"
                            1 => "E&#46; Clappier"
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                  "host" => array:1 [
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                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2005"
                        "volumen" => "106"
                        "paginaInicial" => "274"
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            6 => array:3 [
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              "etiqueta" => "7"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
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