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.
journal_name
Bloodjournal_title
Bloodauthors
Fleischman AG,Aichberger KJ,Luty SB,Bumm TG,Petersen CL,Doratotaj S,Vasudevan KB,LaTocha DH,Yang F,Press RD,Loriaux MM,Pahl HL,Silver RT,Agarwal A,O'Hare T,Druker BJ,Bagby GC,Deininger MWdoi
10.1182/blood-2011-04-348144subject
Has Abstractpub_date
2011-12-08 00:00:00pages
6392-8issue
24eissn
0006-4971issn
1528-0020pii
blood-2011-04-348144journal_volume
118pub_type
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