title: Oncostatin M is a FIP1L1/PDGFRA-dependent mediator of cytokine production in chronic eosinophilic leukemia.
abstract: BACKGROUND
  Chronic eosinophilic leukemia (CEL) is a myeloproliferative neoplasm characterized by expansion of neoplastic eosinophils, tissue infiltration, and organ damage. In a subset of these patients, the FIP1L1/PDGFRA (F/P) oncoprotein is detectable. F/P exhibits constitutive tyrosine kinase activity and activates a number of signaling pathways. So far, however, little is known about the role of F/P-dependent proteins in the pathogenesis of CEL.
  
  
  METHODS
  A screen for F/P-dependent cytokines was performed in growth factor-dependent human cell lines lentivirally transduced with F/P. Signal transduction pathways were characterized in Ba/F3 cells with doxycycline-inducible expression of F/P and in EOL-1 cells. Cytokine expression was confirmed in patients' material by immunohistochemistry, immunofluorescence, and confocal microscopy. Gene expression analysis, proliferation assays, and chemotaxis assays were used to elucidate paracrine interactions between neoplastic eosinophils and stromal cells.
  
  
  RESULTS
  We show that F/P upregulates expression of oncostatin M (OSM) in various cell line models in a STAT5-dependent manner. Correspondingly, neoplastic eosinophils in the bone marrow were found to overexpress OSM. OSM derived from F/P + cells stimulated proliferation of stromal cells. Moreover, OSM-containing supernatants from F/P + cells were found to upregulate production of stromal cell-derived factor-1 (SDF-1)/CXCL12 in human fibroblasts. SDF-1, in turn, induced migration of EOL-1 cells in a dose-dependent manner.
  
  
  CONCLUSIONS
  We have identified a F/P-driven paracrine interaction between neoplastic eosinophils and stromal cells that may contribute to tissue fibrosis and accumulation of neoplastic eosinophils in CEL.
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Hoermann
authors.forename: S
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.forename: I
authors.initials: I
authors.lastname: Sadovnik
authors.forename: L
authors.initials: L
authors.lastname: Müllauer
authors.forename: M
authors.initials: M
authors.lastname: Bilban
authors.forename: M
authors.initials: M
authors.lastname: Gröger
authors.forename: H-P
authors.initials: HP
authors.lastname: Horny
authors.forename: A
authors.initials: A
authors.lastname: Reiter
authors.forename: A
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.forename: C
authors.initials: C
authors.lastname: Mannhalter
authors.forename: P
authors.initials: P
authors.lastname: Valent
authors.forename: M
authors.initials: M
authors.lastname: Mayerhofer
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D053683:Oncostatin M / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation; D039221:mRNA Cleavage and Polyadenylation Factors / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C508351:OSM protein, human; D015514:Oncogene Proteins, Fusion; D050799:STAT5 Transcription Factor; D039221:mRNA Cleavage and Polyadenylation Factors; D053683:Oncostatin M; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha