TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

Proinflammatory cytokines such as TNF alpha are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNF alpha in promoting clonal dominance of JAK2(V617F) expressing cells in MPN. We show that JAK2(V617F) kinase regulates TNF alpha expression in cell lines and primary MPN cells and TNF alpha expression is correlated with JAK2(V617F) allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNF alpha while colony formation by JAK2(V617F)-positive progenitor cells is resistant or stimulated by exposure to TNF alpha. Ectopic JAK2(V617F) expression confers TNF alpha resistance to normal murine progenitor cells and overcomes inherent TNF alpha hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNF alpha 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 TNF alpha resistance to a preneoplastic TNF alpha sensitive cell, while simultaneously generating a TNF alpha-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. (Blood. 2011;118(24):6392-6398)