title: Identification of oncostatin M as a JAK2 V617F-dependent amplifier of cytokine production and bone marrow remodeling in myeloproliferative neoplasms.
abstract: The JAK2 mutation V617F is detectable in a majority of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Enforced expression of JAK2 V617F in mice induces myeloproliferation and bone marrow (BM) fibrosis, suggesting a causal role for the JAK2 mutant in the pathogenesis of MPNs. However, little is known about mechanisms and effector molecules contributing to JAK2 V617F-induced myeloproliferation and fibrosis. We show that JAK2 V617F promotes expression of oncostatin M (OSM) in neoplastic myeloid cells. Correspondingly, OSM mRNA levels were increased in the BM of patients with MPNs (median 287% of ABL, range 22-1450%) compared to control patients (median 59% of ABL, range 12-264%; P < 0.0001). OSM secreted by JAK2 V617F+ cells stimulated growth of fibroblasts and microvascular endothelial cells and induced the production of angiogenic and profibrogenic cytokines (HGF, VEGF, and SDF-1) in BM fibroblasts. All effects of MPN cell-derived OSM were blocked by a neutralizing anti-OSM antibody, whereas the production of OSM in MPN cells was suppressed by a pharmacologic JAK2 inhibitor or RNAi-mediated knockdown of JAK2. In summary, JAK2 V617F-mediated up-regulation of OSM may contribute to fibrosis, neoangiogenesis, and the cytokine storm observed in MPNs, suggesting that OSM might serve as a novel therapeutic target molecule in these neoplasms.
authors: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors: Gregor
authors: G
authors: Hoermann
authors: Sabine
authors: S
authors: Cerny-Reiterer
authors: Harald
authors: H
authors: Herrmann
authors: Katharina
authors: K
authors: Blatt
authors: Martin
authors: M
authors: Bilban
authors: Heinz
authors: H
authors: Gisslinger
authors: Bettina
authors: B
authors: Gisslinger
authors: Leonhard
authors: L
authors: Müllauer
authors: Robert
authors: R
authors: Kralovics
authors: Christine
authors: C
authors: Mannhalter
authors: Peter
authors: P
authors: Valent
authors: Matthias
authors: M
authors: Mayerhofer
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D055785:Gene Knockdown Techniques; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D053683:Oncostatin M / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055728:Primary Myelofibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013920:Thrombocythemia, Essential / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D050505:Mutant Proteins; C508351:OSM protein, human; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D053683:Oncostatin M; D019869:Phosphatidylinositol 3-Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2