Impact of isolated germline JAK2V617I mutation on human hematopoiesis

Abstract

Key Points• Germline JAK2V617I mutation as a sole genetic event does not suppress hematopoietic stem cells.• JAK2V617I induces weaker constitutive activation than JAK2V617F but considerable cytokine hyperresponsiveness.The association between somatic JAK2 mutation and myeloproliferative neoplasms (MPNs) is now well established. However, because JAK2 mutations are associated with heterogeneous clinical phenotypes and often occur as secondary genetic events, some aspects of JAK2 mutation biology remain to be understood. We recently described a germline JAK2V617I mutation in a family with hereditary thrombocytosis and herein characterize the hematopoietic and signaling impact of JAK2V617I. Through targeted sequencing of MPN-associated mutations, exome sequencing, and clonality analysis, we demonstrate that JAK2V617I is likely to be the sole driver mutation in JAK2V617I-positive individuals with thrombocytosis. Phenotypic hematopoietic stem cells (HSCs) were increased in the blood and bone marrow of JAK2V617I-positive individuals and were sustained at higher levels than controls after xenotransplantation. In signaling and transcriptional assays, JAK2V617I demonstrated more activity than wild-type JAK2 but substantially less than JAK2V617F. After cytokine stimulation, JAK2V617I resulted in markedly increased downstream signaling compared with wild-type JAK2 and comparable with JAK2V617F. These findings demonstrate that JAK2V617I induces sufficient cytokine hyperresponsiveness in the absence of other molecular events to induce a homogeneous MPN-like phenotype. We also provide evidence that the JAK2V617I mutation may expand the HSC pool, providing insights into both JAK2 mutation biology and MPN disease pathogenesis. (Blood. 2013;121(20):4156-4165)

A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis

“…Recently, familial thrombocytosis has been associated with a germline MPL mutation 37 and a TET2 truncation mutation, 38 but evidence so far has shown that JAK2 mutations, particularly JAK2V 617 F, are acquired independently by individuals. Although 2 recent reports have associated a germline JAK2V 617 I mutation with familial thrombocytosis, 22,23 our study is the first to demonstrate the contribution of a novel germline mutation involving an alternative JAK2 residue to MPN development and to outline the potential mechanisms responsible for causing familial thrombocytosis. We hypothesize that the JAK2R 564 Q mutation prevents apoptosis in hematopoietic stem cells and megakaryocyte progenitors, giving rise to a moderate increase in platelets.…”

“…To date, only a single other inherited JAK2 mutation has been suggested to be responsible for the development of MPN, 22,23 and this involved an Ile substitution of the well-studied Val 617 residue. Here we describe a novel germline mutation of JAK2 associated with familial ET that does not involve Val 617 but, rather, an alternative residue in the same JH2 domain, Arg 564 .…”

“…The single exception is JAK2V 617 I, recently proposed as a germline mutation associated with hereditary thrombocytosis. 22,23 Here we describe for the first time a JAK2 mutation associated with a familial MPN that involves a residue other than Val 617 . This novel mutation in exon 13 of JAK2 is a single nucleotide substitution, g1691a, which results in an arginine to glutamine change at position 564 (JAK2R 564 Q).…”

Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors

“…8 Likewise, 2 germ-line mutations, JAK2 V617I (different from the V617F substitution classically found in 60% of sporadic essential thrombocythemias [ETs]) and JAK2 R564Q (never observed in sporadic MPNs), have been reported. [9][10][11] Several mutations in the TPO gene that lead to increased TPO translation have also been described in families with a thrombocytosis. [12][13][14][15] Here, we report 2 families with hereditary thrombocytosis carrying so far unidentified heterozygous germ-line mutations in JAK2.…”

JAK2 mutations to the fore in hereditary thrombocythemia

“…6,7 Alternatively, the V617I appears to be sufficient to induce a HT phenotype in a qualitatively distinct manner to that of V617F. 8 Identification of the rare HT is also clinically important as an increased risk of thrombotic/hemorrhagic events, splenomegaly, bone marrow fibrosis, and also transformation to acute myeloid leukemia has been noted in previously documented HT kindred. 9,10 Therefore, these recent reports of germline JAK2 mutations in HT compel the incorporation of JAK2 gene analysis, including at least those exons that encode the pseudo-kinase and kinase domains, into the molecular diagnostic algorithm for suspected HT.…”