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.—Hoermann, G., Cerny‐Reiterer, S., Herrmann, H., Blatt, K., Bilban, M., Gisslinger, H., Gisslinger, B., Müllauer, L., Kralovics, R., Mannhalter, C., Valent, P., Mayerhofer, M. Identification of oncostatin M as a JAK2 V617F‐dependent amplifier of cytokine production and bone marrow remodeling in myeloproliferative neoplasms. FASEB J. 26, 894–906 (2012). www.fasebj.org