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
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    • "We asked whether the large EpoR distances and different binding geometries induced by the diabodies could modulate the activity of these kinase mutants in an extracellular ligand-dependent manner by separating the two JAKs at distances where they could not undergo transactivation . The JAK2V617F mutant is the best-described example of an oncogenic JAK mutation, causing the development of hematological disorders such as polycythemia vera (PV) and other myeloproliferative (MPN) neoplasms (Baxter et al., 2005; James et al., 2005; Kralovics et al., 2005; Levine et al., 2005). At physiologic expression levels, JAK2V617F-pos- itive cells require EpoR to proliferate in a ligand-independent manner (Lu et al., 2008). "
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    • "Gripp et al. [2013] described a two-year-old child with myelofibrosis, a myeloproliferative disorder rarely occurring in children [Tefferi and Vardiman, 2008]. Of note, the disorder was not associated with mutations in JAK2 [Kralovics et al., 2005]. Ekvall et al. [2011] reported on a child diagnosed with a spinal neuroblastoma as a newborn. "
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