title: TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms.
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.
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA. fleischm@ohsu.edu
authors.forename: Angela G
authors.initials: AG
authors.lastname: Fleischman
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Aichberger
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Luty
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Bumm
authors.forename: Curtis L
authors.initials: CL
authors.lastname: Petersen
authors.forename: Shirin
authors.initials: S
authors.lastname: Doratotaj
authors.forename: Kavin B
authors.initials: KB
authors.lastname: Vasudevan
authors.forename: Dorian H
authors.initials: DH
authors.lastname: LaTocha
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Press
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.forename: Heike L
authors.initials: HL
authors.lastname: Pahl
authors.forename: Richard T
authors.initials: RT
authors.lastname: Silver
authors.forename: Anupriya
authors.initials: A
authors.lastname: Agarwal
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C507924:JAK2 protein, human; D053614:Janus Kinase 2