Genetically defined EWS/FLI1 model system suggests mesenchymal origin of Ewing's family tumors

Abstract

Ewing's family tumors (EFTs) are characterized by recurrent chromosomal translocations that produce chimeric fusions between the EWS gene and one of five ETS transcription factors. The expression of EWS/FLI1, the predominant fusion product in EFTs, is believed to deregulate downstream target genes in an undefined tissue type and leads to development of EFTs. Attempts to generate model systems that represent EFTs have been hampered by an unexpected toxicity of the fusion gene. In the present study, we used gene expression analysis to identify tissue types based on the similarity of their expression profiles to those of EWS/FLI1-modulated genes. The data obtained from this screen helped to identify IMR-90 cells, a human fetal fibroblast, that upon further manipulation can maintain stable EWS/FLI1 expression without the reported toxicity. In addition, gene expression profiling of these cells revealed a significant overlap of genes that have been previously reported to be targets of EWS/FLI1. Furthermore, we show, for the first time, a partial transformation of these human primary fibroblasts with EWS/FLI1 expression. The experiments presented here provide a solid foundation for generation of a new model system for studying Ewing's sarcoma biology. © 2008 USCAP, Inc All rights reserved.