title: Development of Ewing's sarcoma from primary bone marrow-derived mesenchymal progenitor cells.
abstract: Ewing's sarcoma is a member of Ewing's family tumors (EFTs) and the second most common solid bone and soft tissue malignancy of children and young adults. It is associated in 85% of cases with the t(11;22)(q24:q12) chromosomal translocation that generates fusion of the 5' segment of the EWS gene with the 3' segment of the ETS family gene FLI-1. The EWS-FLI-1 fusion protein behaves as an aberrant transcriptional activator and is believed to contribute to EFT development. However, EWS-FLI-1 induces growth arrest and apoptosis in normal fibroblasts, and primary cells that are permissive for its putative oncogenic properties have not been discovered, hampering basic understanding of EFT biology. Here, we show that EWS-FLI-1 alone can transform primary bone marrow-derived mesenchymal progenitor cells and generate tumors that display hallmarks of Ewing's sarcoma, including a small round cell phenotype, expression of EFT-associated markers, insulin like growth factor-I dependence, and induction or repression of numerous EWS-FLI-1 target genes. These observations provide the first identification of candidate primary cells from which EFTs originate and suggest that EWS-FLI-1 expression may constitute the initiating event in EFT pathogenesis.
authors.affiliation: Experimental Pathology Division, Institute of Pathology, University of Lausanne, Switzerland.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Riggi
authors.forename: Luisa
authors.initials: L
authors.lastname: Cironi
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.forename: Mario-Luca
authors.initials: ML
authors.lastname: Suvà
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kaloulis
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Francesco
authors.initials: F
authors.lastname: Hoffmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.forename: Ivan
authors.initials: I
authors.lastname: Stamenkovic
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001854:Bone Marrow Cells / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010641:Phenotype; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I