Abstract
Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2(V617F) expressing cells in MPN. We show that JAK2(V617F) kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2(V617F) allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2(V617F)-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2(V617F) expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα 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 TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Animals
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Cell Line, Tumor
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Cell Transformation, Neoplastic / metabolism*
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Cells, Cultured
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Fanconi Anemia Complementation Group C Protein / genetics
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Fanconi Anemia Complementation Group C Protein / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Janus Kinase 2 / antagonists & inhibitors
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism*
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Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / blood
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Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / drug therapy
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Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / genetics
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Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / metabolism
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Mice
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Mice, Knockout
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Mutant Proteins / metabolism
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Myeloid Progenitor Cells / metabolism
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Myeloproliferative Disorders / blood
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Myeloproliferative Disorders / drug therapy
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Myeloproliferative Disorders / genetics
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Myeloproliferative Disorders / metabolism*
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Point Mutation
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Protein Kinase Inhibitors / pharmacology
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RNA, Messenger / metabolism
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Recombinant Proteins / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Fancc protein, mouse
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Fanconi Anemia Complementation Group C Protein
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Mutant Proteins
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Protein Kinase Inhibitors
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RNA, Messenger
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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JAK2 protein, human
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Janus Kinase 2