title: The Ewing's sarcoma fusion protein, EWS-FLI, binds Runx2 and blocks osteoblast differentiation.
abstract: Ewing's sarcomas are highly aggressive round cell tumors of bone and soft tissues that afflict children and young adults. The majority of these tumors harbor the t(11;22) translocation and express the fusion protein EWS-FLI. Modern molecular profiling experiments indicate that Ewing's tumors originate from mesenchymal precursors in young individuals. EWS-FLI alters the morphology of mesenchymal cells and prevents lineage specification; however, the molecular mechanisms for differentiation arrest are unclear. We recently showed that EWS-FLI binds Runx2, a master regulator of osteoblast differentiation. In this report, we demonstrate that FLI sequences within EWS-FLI are responsible for interactions with Runx2. EWS-FLI blocks the expression of osteoblastic genes in a multipotent progenitor cell line that requires Runx2 to integrate bone morphogenic protein (Bmp)2 signaling while increasing proliferation and altering cell morphology. These results demonstrate that EWS-FLI blocks the ability of Runx2 to induce osteoblast specification of a mesenchymal progenitor cell. Disrupting interactions between Runx2 and EWS-FLI1 may promote differentiation of the tumor cell.
authors.affiliation: Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Meghan E
authors.initials: ME
authors.lastname: McGee-Lawrence
authors.forename: Matthew
authors.initials: M
authors.lastname: Decker
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D048430:Cell Shape; D050659:Core Binding Factor Alpha 1 Subunit / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism*; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D002148:Calmodulin-Binding Proteins; D050659:Core Binding Factor Alpha 1 Subunit; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS