title: EWS-FLI1 induces developmental abnormalities and accelerates sarcoma formation in a transgenic mouse model.
abstract: Ewing's sarcoma is characterized by the t(11;22)(q24:q12) reciprocal translocation. To study the effects of the fusion gene EWS-FLI1 on development and tumor formation, a transgenic mouse model was created. A strategy of conditional expression was used to limit the potentially deleterious effects of EWS-FLI1 to certain tissues. In the absence of Cre recombinase, EWS-FLI1 was not expressed in the EWS-FLI1 transgenic mice, and they had a normal phenotype. When crossed to the Prx1-Cre transgenic mouse, which expresses Cre recombinase in the primitive mesenchymal cells of the embryonic limb bud, the EF mice were noted to have a number of developmental defects of the limbs. These included shortening of the limbs, muscle atrophy, cartilage dysplasia, and immature bone. By itself, EWS-FLI1 did not induce the formation of tumors in the EF transgenic mice. However, in the setting of p53 deletion, EWS-FLI1 accelerated the formation of sarcomas from a median time of 50 to 21 weeks. Furthermore, EWS-FLI1 altered the type of tumor that formed. Conditional deletion of p53 in mesenchymal cells (Prx1-Cre p53(lox/lox)) produced osteosarcomas as the predominant tumor. The presence of EWS-FLI1 shifted the tumor phenotype to a poorly differentiated sarcoma. The results taken together suggest that EWS-FLI1 inhibits normal limb development and accelerates the formation of poorly differentiated sarcomas.
authors.affiliation: Department of Orthopaedic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. plin@mdanderson.org
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Lin
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Pandey
authors.forename: Fenghua
authors.initials: F
authors.lastname: Jin
authors.forename: Shunbin
authors.initials: S
authors.lastname: Xiong
authors.forename: Michael
authors.initials: M
authors.lastname: Deavers
authors.forename: John M
authors.initials: JM
authors.lastname: Parant
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division; D017931:DNA Primers; D007150:Immunohistochemistry; D017880:Limb Deformities, Congenital / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012513:Sarcoma, Experimental / Q000235:genetics / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors