Coexistence of JAK2V617F mutation and isolated del(5q) in a patient with thrombocytosis

Marcé, Silvia; Ruiz-Xivillé, Neus; Arenillas, Leonor

doi:10.1016/j.medcli.2020.04.065

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Immunohistochemistry techniques in the bone marrow biopsy showed the presence of monolobated nuclei megakaryocytes with CD61 staining (C) and grade II fibrosis with reticulin stain (D), both highlighted with arrows. JAK2V617F mutation by ASO-PCR (E) and fluorescence in situ hybridization (FISH) (F) demonstrating the absence of del(5q) (two control signals in 5p15.2 and two signals for 5q31 region) in all the red colonies studied." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Silvia Marcé, Neus Ruiz-Xivillé, Leonor Arenillas" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Silvia" "apellidos" => "Marcé" ] 1 => array:2 [ "nombre" => "Neus" "apellidos" => "Ruiz-Xivillé" ] 2 => array:2 [ "nombre" => "Leonor" "apellidos" => "Arenillas" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S0025775320304875" "doi" => "10.1016/j.medcli.2020.04.065" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775320304875?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020621002539?idApp=UINPBA00004N" "url" => "/23870206/0000015600000012/v1_202106160926/S2387020621002539/v1_202106160926/en/main.assets" ] ] "itemSiguiente" => array:18 [ "pii" => "S002577532030467X" "issn" => "00257753" "doi" => "10.1016/j.medcli.2020.05.032" "estado" => "S300" "fechaPublicacion" => "2021-06-25" "aid" => "5300" "copyright" => "Elsevier España, S.L.U." 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Immunohistochemistry techniques in the bone marrow biopsy showed the presence of monolobated nuclei megakaryocytes with CD61 staining (C) and grade II fibrosis with reticulin stain (D), both highlighted with arrows. JAK2V617F mutation by ASO-PCR (E) and fluorescence in situ hybridization (FISH) (F) demonstrating the absence of del(5q) (two control signals in 5p15.2 and two signals for 5q31 region) in all the red colonies studied." ] ] ] "textoCompleto" => "Interstitial deletion of chromosome 5q is the most common cytogenetic abnormality in myelodisplastic syndromes (MDS). Patients with MDS isolated del(5q) have a refractory macrocytic anemia with or without other cytopenias and/or thrombocytosis, displastyc megakaryocytes and an indolent clinical course.<a class="elsevierStyleCrossRefs" href="#bib0030">1,2</a> Isolated del(5q) can occur also in myeloid malignancies including myeloproliferative neoplasms (MPN).<a class="elsevierStyleCrossRef" href="#bib0030">1</a>The JAK2V617F mutation is a frequent event in a large proportion of patients with MPN. Essential thrombocythemia (ET) is a MPN characterized by sustained thrombocytosis in the peripheral blood, increased number of large mature megakaryocytes in the bone marrow and by episodes of thrombosis and/or hemorrhage. Primary myelofibrosis (PMF) is the most frequent MPN associated with del(5q) and increased grade of reticulin fibrosis (grade III or more) in the bone marrow. However, JAK2V617F mutation is rare in other hematopoietic disorders, except in MDS with myelofibrosis, suggesting a myeloproliferative nature in a subset of MDS patients.<a class="elsevierStyleCrossRefs" href="#bib0040">3,4</a>Here we present an 82-year-old woman with persistent thrombocytosis and an increased proportion of megakaryocytes, some of them of big size and hyperlobulated nuclei, and others of small size and monolobated nuclei (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A and B). Conventional cytogenetic revealed the presence of del(5)(q12;q33) and molecular studies demonstrated the JAK2V617F mutation. The biopsy obtained during the clinical course demonstrated augmented cellularity with decreased fat marrow and presence of grade II reticulin fibrosis with some focus of collagen fibrosis that suggests that it could be a consequence of the progression of an ET. It also showed a megakaryocytic hyperplasia with dysplastic features and monolobated nuclei megakaryocytes (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C and D), postulating the existence of a MDS with isolated del(5q). Due to the suspicion of the coexistence of two hematological entities, we cultured in vitro erythroid burst-forming units (BFU-E) showing that 100% of the colonies harbored the JAK2V617F mutation. Simultaneously, fluorescence in situ hybridization (FISH) with a chromosome 5q31 deletion probe was also performed in these colonies and we could not demonstrate the 5q deletion in any of them (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>E and F), suggesting that both alterations may derive from genetically independent clones (MDS with isolated (5q) clone and NMP clone), and that only the most proliferative cells grew in the culture.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The concomitant presence of del(5q) and JAK2V617F mutation is a rare event which occurs prevalently in patients with a possibly MDS and MPN coexistence. Some studies investigated the clonal origin of JAK2V617F mutation in a patient with del(5q). Interestingly, they found that not all del(5q) cells were JAK2V617F positive suggesting that both alterations may derive from genetically independent clones. Ingram et al.<a class="elsevierStyleCrossRef" href="#bib0050">5</a> evidenced that JAK2V617F appeared earlier in these patients arising in a pluripotent stem cell and that del(5q) may be present in the same CD34+ cells though not all del(5q) cells are JAK2V617F positive. Sokol et al.<a class="elsevierStyleCrossRef" href="#bib0035">2</a> detected JAK2V617F mutant in two distinct multipotent stem cell progeny that lacked del(5q) indicating that JAK2V617F and del(5q) derived from independent clones, as we observed in our patient. Nevertheless, this does not exclude the possibility that both clones derived from a genetically unstable hierarchal stem cell. Cytogenetic and molecular genetics show overlaps in some MDS and MPN cases which indicate common pathways in the etiology of both disorders.<a class="elsevierStyleCrossRef" href="#bib0045">4</a> A literature review indicated that isolated deletion of 5q is uncommon in JAK2V617F positive ET but, when deletion is present, the disease often shows mixed features of both ET and MDS with isolated del(5q).<a class="elsevierStyleCrossRef" href="#bib0045">4</a>In conclusion, BFU-E study may help to identify one neoplasm with two alterations or two genetically independent entities in cases with JAK2V617F and del(5q). The presence of del(5q) and JAK2V617F in patients combining both MDS and MPN requires further biological and clinical studies and longer follow-up to determine the prognosis of these patients. However, the combination of molecular, cytogenetic and colonies cell cultures studies in these patients may help to improve clinical management and biological knowledge.FundingThis work was supported in part by a grant from Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain (PI 11/02519); 2014 SGR225 (GRE) Generalitat de Catalunya; Fundació Josep Carreras and Celgene Spain.Conflict of interestAuthors may describe any financial or personal relationship which can cause a conflict of interest regarding this article." 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Immunohistochemistry techniques in the bone marrow biopsy showed the presence of monolobated nuclei megakaryocytes with CD61 staining (C) and grade II fibrosis with reticulin stain (D), both highlighted with arrows. JAK2V617F mutation by ASO-PCR (E) and fluorescence in situ hybridization (FISH) (F) demonstrating the absence of del(5q) (two control signals in 5p15.2 and two signals for 5q31 region) in all the red colonies studied." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "WHO classification of tumours of haematopoietic and lymphoid tissues" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.H. Swerdlow" 1 => "E. Campo" 2 => "N.L. Harris" 3 => "E.S. Jaffe" 4 => "S.A. 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Richebourg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3324/haematol.2011.053918" "Revista" => array:6 [ "tituloSerie" => "Haematologica" "fecha" => "2012" "volumen" => "97" "paginaInicial" => "1036" "paginaFinal" => "1041" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22532522" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0045" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Distribution of cytogenetic abnormalities in myelodysplastic syndromes. Philadelphia negative myeloproliferative neoplasms, and the overlap MDS/MPN category" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "U. Bacher" 1 => "S. Schnittger" 2 => "W. Kern" 3 => "T. Weiss" 4 => "T. Haferlach" 5 => "C. Haferlach" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00277-009-0745-3" "Revista" => array:6 [ "tituloSerie" => "Ann Hematol" "fecha" => "2009" "volumen" => "88" "paginaInicial" => "1207" "paginaFinal" => "1213" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19415278" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated 5q and a proliferative bone marrow" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "W. Ingram" 1 => "N.C. Lea" 2 => "J. Cervera" 3 => "U. Germing" 4 => "P. Fenaux" 5 => "B. Cassinat" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.leu.2404215" "Revista" => array:6 [ "tituloSerie" => "Leukemia" "fecha" => "2006" "volumen" => "20" "paginaInicial" => "1319" "paginaFinal" => "1321" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16617322" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack535209" "titulo" => "Acknowledgments" "texto" => "The authors would like to thank Diana Domínguez, Lurdes Zamora, Lourdes Florensa, Marta Cabezón, Alberto Pineda, Gustavo Tapia and José Tomás Navarro for their contribution to this publication." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/00257753/0000015600000012/v1_202106110528/S0025775320304875/v1_202106110528/en/main.assets" "Apartado" => array:4 [ "identificador" => "66447" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Cartas científicas" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/00257753/0000015600000012/v1_202106110528/S0025775320304875/v1_202106110528/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775320304875?idApp=UINPBA00004N"]

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