Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms

Abstract

Key Points Germ line variants in TERT, SH2B3, TET2, ATM, CHEK2, PINT, and GFI1B are associated with JAK2 V617F clonal hematopoiesis and MPNs. Age-related JAK2 V617F clonal hematopoiesis is found in ∼2 out of 1000 individuals in the general population.

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

“…Furthermore, it cannot be ruled out whether an inherited mutation in one of the alleles may be accompanied by an epigenomic inactivation of the other otherwise normal alleles rendering the cell biological homozygous. What seems clear, however, and the present data contributes to this conclusion, is that the role of the JAK2 V617F mutation in the pathogenicity of the different MPNs may differ amongst different MPNs requiring the JAK2 V617F mutation more often than others (e.g., ET vs. PV), which would indicate other oncogenic mutations that may be relevant for certain cases others than JAK2 V617F (16,33,58,59).…”

“…Besides mutations and other molecular abnormalities, various factors, such as gene burden and individual genetic background, may influence the predisposition for developing an MPN, as well as their heterogeneity (16,57). Although JAK2 V617F homozygous subclones are present in PV and ET patients, the expansion of a dominant homozygous subclone occurs almost exclusively in PV patients (~80% in PV and 50% in ET) (33,57), due to either additional genetic or epigenetic events or non-cell-autonomous selective pressures, such as low levels of circulating erythropoietin in the context of elevated hematocrit (33).…”

“…For example, the V617F allele burden tends to be higher in PV and PMF, and is associated with the presence of acquired uniparental disomy (UPD), whereas a lower allele burden is generally observed in ET patients (7,16,33,37,38).…”

“…Although it is possible to identify one of these mutations in the majority of the BCR/ ABL-negative disorder patients, there are unidentified genetic defects in approximately 10-15% of cases, predominantly of ET and PMF and, furthermore, those mutations cannot fully explain the phenotypic heterogeneity of PN-MPNs nor the susceptibility of progression to myelofibrosis, acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS) (16). In addition, the cellular and molecular mechanisms involved in the pathophysiology of MPNs have not yet been fully clarified (16,(19)(20)(21)(22)(23)(24)(25)(26). It is well known that hematopoietic cytokine receptor signaling is largely mediated by JAKs, a family of tyrosine kinases, and their downstream transcription factors, termed signal transducer and activator of transcription (STAT).…”

“…According to the available studies, the frequencies of these mutations are ~95, 0, and 0% in PV, 60, 3, and 20% in ET, and 60, 7, and 25% in PMF, respectively (6,(14)(15)(16)(17)(18). Although it is possible to identify one of these mutations in the majority of the BCR/ ABL-negative disorder patients, there are unidentified genetic defects in approximately 10-15% of cases, predominantly of ET and PMF and, furthermore, those mutations cannot fully explain the phenotypic heterogeneity of PN-MPNs nor the susceptibility of progression to myelofibrosis, acute myeloid leukaemia (AML) or myelodysplastic syndromes (MDS) (16). In addition, the cellular and molecular mechanisms involved in the pathophysiology of MPNs have not yet been fully clarified (16,(19)(20)(21)(22)(23)(24)(25)(26).…”