title: Identification of oncostatin M as a STAT5-dependent mediator of bone marrow remodeling in KIT D816V-positive systemic mastocytosis.
abstract: Systemic mastocytosis is a neoplastic disease of mast cells harboring the activating KIT mutation D816V. In most patients, mast cell infiltration in the bone marrow is accompanied by marked microenvironment alterations, including increased angiogenesis, osteosclerosis, and sometimes fibrosis. Little is known about the mast cell-derived molecules contributing to these bone marrow alterations. We show here that neoplastic mast cells in patients with systemic mastocytosis express oncostatin M (OSM), a profibrogenic and angiogenic modulator. To study the regulation of OSM expression, KIT D816V was inducibly expressed in Ba/F3 cells and was found to up-regulate OSM mRNA and protein levels, suggesting that OSM is a KIT D816V-dependent mediator. Correspondingly, KIT D816V(+) HMC-1.2 cells expressed significantly higher amounts of OSM than the KIT D816V(-) HMC-1.1 subclone. RNA interference-induced knockdown of STAT5, a key transcription factor in KIT D816V(+) mast cells, inhibited OSM expression in HMC-1 cells, whereas a constitutively activated STAT5 mutant induced OSM expression. Finally, OSM secreted from KIT D816V(+) mast cells stimulated growth of endothelial cells, fibroblasts, and osteoblasts, suggesting that mast cell-derived OSM may serve as a key modulator of the marrow microenvironment and thus contribute to the pathology of systemic mastocytosis.
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: Andrea
authors: A
authors: Perné
authors: Miriam
authors: M
authors: Klauser
authors: Konrad
authors: K
authors: Hoetzenecker
authors: Katharina
authors: K
authors: Klein
authors: Leonhard
authors: L
authors: Müllauer
authors: Marion
authors: M
authors: Gröger
authors: Sebastian M B
authors: SM
authors: Nijman
authors: Walter
authors: W
authors: Klepetko
authors: Peter
authors: P
authors: Valent
authors: Matthias
authors: M
authors: Mayerhofer
mesh_terms: D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation; D053683:Oncostatin M / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: C508351:OSM protein, human; D050799:STAT5 Transcription Factor; D053683:Oncostatin M; D019009:Proto-Oncogene Proteins c-kit