RESUMO
Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPORP488S ) in a large family diagnosed with JAK2V617F -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPORP488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited-risk alleles affecting the JAK2/STAT pathway in MPN.
Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Receptores da Eritropoetina , Trombocitemia Essencial , Alelos , Mutação com Ganho de Função , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Mutação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Policitemia Vera/genética , Receptores da Eritropoetina/genética , Trombocitemia Essencial/genéticaRESUMO
The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.
Assuntos
Proteínas Relacionadas à Autofagia/genética , Cromossomos Humanos Par 14/genética , Hematopoiese Clonal , Duplicação Gênica , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/patologia , Proteínas Repressoras/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Suscetibilidade a Doenças , Feminino , Seguimentos , Células Germinativas , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induced pluripotent stem cells and primary cells, we demonstrate that overexpression of ATG2B and GSKIP enhances hematopoietic progenitor differentiation, including of megakaryocytes, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication may change the fitness of cells harboring signaling pathway mutations and increases the probability of disease development.
Assuntos
Duplicação Gênica , Predisposição Genética para Doença , Células Germinativas , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Proteínas Repressoras/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Idoso , Proteínas Relacionadas à Autofagia , Criança , Cromossomos Humanos Par 14 , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Lactente , Masculino , Linhagem , Fenótipo , Adulto JovemRESUMO
The JAK2(V617F) mutation does not elucidate the phenotypic variability observed in myeloproliferative neoplasm (MPN) families. A putative tumor suppressor gene, TET2, was recently implicated in MPN and myelodysplastic syndromes through the identification of acquired mutations affecting hematopoietic stem cells. The present study analyzed the TET2 gene in 61 MPN cases from 42 families. Fifteen distinct mutations were identified in 12 (20%) JAK2(V617F)-positive or -negative patients. In a patient with 2 TET2 mutations, the analysis of 5 blood samples at different phases of her disease showed the sequential occurrence of JAK2(V617F) and TET2 mutations concomitantly to the disease evolution. Analysis of familial segregation confirmed that TET2 mutations were not inherited but somatically acquired. TET2 mutations were mainly observed (10 of 12) in patients with primary myelofibrosis or patients with polycythemia vera or essential thrombocythemia who secondarily evolved toward myelofibrosis or acute myeloid leukemia.