A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders

University of Pavia, Ticinum, Lombardy, Italy
New England Journal of Medicine (Impact Factor: 55.87). 05/2005; 352(17):1779-90. DOI: 10.1056/NEJMoa051113
Source: PubMed


Polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are clonal myeloproliferative disorders arising from a multipotent progenitor. The loss of heterozygosity (LOH) on the short arm of chromosome 9 (9pLOH) in myeloproliferative disorders suggests that 9p harbors a mutation that contributes to the cause of clonal expansion of hematopoietic cells in these diseases.
We performed microsatellite mapping of the 9pLOH region and DNA sequencing in 244 patients with myeloproliferative disorders (128 with polycythemia vera, 93 with essential thrombocythemia, and 23 with idiopathic myelofibrosis).
Microsatellite mapping identified a 9pLOH region that included the Janus kinase 2 (JAK2) gene. In patients with 9pLOH, JAK2 had a homozygous G-->T transversion, causing phenylalanine to be substituted for valine at position 617 of JAK2 (V617F). All 51 patients with 9pLOH had the V617F mutation. Of 193 patients without 9pLOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65 percent among patients with polycythemia vera (83 of 128), 57 percent among patients with idiopathic myelofibrosis (13 of 23), and 23 percent among patients with essential thrombocythemia (21 of 93). V617F is a somatic mutation present in hematopoietic cells. Mitotic recombination probably causes both 9pLOH and the transition from heterozygosity to homozygosity for V617F. Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages. Patients with the V617F mutation had a significantly longer duration of disease and a higher rate of complications (fibrosis, hemorrhage, and thrombosis) and treatment with cytoreductive therapy than patients with wild-type JAK2.
A high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.

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Available from: Andreas Buser, Aug 25, 2014
    • "The JAKs play critical roles in several important intracellular signaling pathways, including the eponymous JAK/STAT pathway, central to the mediation of cytokine signaling [3]. Somatic mutation of JAK2 (V617F), has recently been identified in patients with polycythemia vera, essential thrombocytosis [7] and myelofibrosis [4], hematopoietic malignancies, including auto-immune diseases, myeloproliferative syndromes [8] [9] [10] [11] leukemias [12] [13] and lymphomas [14] as well as cardiovascular disease [15]. This mutation results in a constitutively active JAK2 tyrosine kinase. "
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