A Constitutively Active JAK2 Mutant Underlies Polycythemia Vera

Abstract

Polycythemia vera is a clonal disorder of hematopoietic stem cells in which there is excessive production of red blood cells and other myeloid cell types; the progenitor cells are hyperresponsive to erythropoietin and other cytokines. James et al. used siRNA to decrease the expression in cells from polycythemia vera patients of JAK2, a nonreceptor tyrosine kinase implicated in erythropoietin receptor (EpoR) signaling, and found that this manipulation inhibited spontaneous erythroid differentiation and cytokine-independent formation of erythroid colonies. Sequence analysis revealed a valine to phenylalanine substitution at JAK2 amino acid position 617 in cells of myeloid lineage from 40 of 45 people with polycythemia vera and none of 15 people without the disorder. When transfected into a line of cells that lacked JAK2, mutant JAK2 transcriptionally activated a STAT5-dependent gene reporter in the absence of erythropoietin and independent of EpoR expression. Mutant JAK2 also induced growth factor-independent survival and proliferation in three cell lines; hypersensitivity to erythropoietin was apparent in two lines that expressed the EpoR. Mice transplanted with murine bone marrow cells carrying the V617F JAK2 mutant developed erythrocytosis. The mutation also appeared in cells from people with two other myeloproliferative disorders, essential thrombocythemia and idiopathic myelofibrosis. Thus, a mutation that leads to constitutive activation of JAK2 signaling appears to underlie the pathogenesis of polycythemia vera, suggesting that JAK2 may be an appropriate target for therapeutic intervention in polycythemia vera and related myeloproliferative disorders. C. James, V. Ugo, J.-P. Le Couédic, J. Staerk, F. Delhommeau, C. Lacout, L. Garçon, H. Raslova, R. Berger, A. Bennaceur-Griscelli, J. L. Villeval, S. N. Constantinescu, N. Casadevall, W. Vainchenker, A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434 , 1144-1148 (2005). [PubMed]