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Identification of oncostatin M as a JAK2 V617F-dependent amplifier of cytokine production and bone marrow remodeling in myeloproliferative neoplasms.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2012 Feb; Vol. 26 (2), pp. 894-906. Date of Electronic Publication: 2011 Nov 03. - Publication Year :
- 2012
-
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.
- Subjects :
- Amino Acid Substitution
Animals
Base Sequence
Bone Marrow metabolism
Bone Marrow pathology
Case-Control Studies
Cell Line
Cytokines biosynthesis
Gene Knockdown Techniques
Humans
Janus Kinase 2 antagonists & inhibitors
Mice
Mutation, Missense
Myeloproliferative Disorders pathology
Neovascularization, Pathologic
Oncostatin M blood
Oncostatin M genetics
Phosphatidylinositol 3-Kinases metabolism
Polycythemia Vera genetics
Polycythemia Vera metabolism
Polycythemia Vera pathology
Primary Myelofibrosis genetics
Primary Myelofibrosis metabolism
Primary Myelofibrosis pathology
RNA, Messenger genetics
RNA, Messenger metabolism
STAT5 Transcription Factor metabolism
Thrombocythemia, Essential genetics
Thrombocythemia, Essential metabolism
Thrombocythemia, Essential pathology
Janus Kinase 2 genetics
Janus Kinase 2 metabolism
Mutant Proteins genetics
Mutant Proteins metabolism
Myeloproliferative Disorders genetics
Myeloproliferative Disorders metabolism
Oncostatin M metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 26
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 22051730
- Full Text :
- https://doi.org/10.1096/fj.11-193078