TNFalpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms.

摘要

Proinflammatory cytokines such as TNFalpha are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFalpha in promoting clonal dominance of JAK2(V617F) expressing cells in MPN. We show that JAK2(V617F) kinase regulates TNFalpha expression in cell lines and primary MPN cells and TNFalpha expression is correlated with JAK2(V617F) allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFalpha while colony formation by JAK2(V617F)-positive progenitor cells is resistant or stimulated by exposure to TNFalpha. Ectopic JAK2(V617F) expression confers TNFalpha resistance to normal murine progenitor cells and overcomes inherent TNFalpha hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFalpha limits clonal expansion and attenuates disease in a murine model of JAK2(V617F)-positive MPN. Altogether our data are consistent with a model where JAK2(V617F) promotes clonal selection by conferring TNFalpha resistance to a preneoplastic TNFalpha sensitive cell, while simultaneously generating a TNFalpha-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.