EWS-FLI1 in Ewing's sarcoma: real targets and collateral damage.
Ewing's sarcoma family of tumors (ESFT) are a clinically and scientifically very demanding group of tumors in children and young adults with still unknown histogenesis. The rate-limiting oncogenic mutation in this disease has been identified as a chromosomal translocation, t(11;22)(q24;q12), that leads to the expression of a chimeric transcription factor, EWS-FLI1. We have studied the downstream pathway of EWS-FLI1 by a dual strategy including the isolation of direct target genes from ESFT chromatin and the monitoring of transcriptomic changes after silencing of EWS-FLI1 by RNA interference. This study has lead to the identification of several directly EWS-FLI1-regulated genes and the characterization of their genomic distribution. By comparing several ESFT cell lines, not only variation in overall gene expression patterns downstream of EWS-FLIl was observed, but also differential regulation of directly EWS-FLI1-bound genes. Interestingly, there was variation between members of the same functional gene families. Studies on CD99, another diagnostic hallmark of ESFT, in relation to EWS-FLI1 provided additional evidence for context dependence of fusion protein function. Together, our study represents a first approach to the separation of essential molecular consequences from noise generated by the EWS-FLI1 gene rearrangement in ESFT.
Ban
Jozef
J
Children's Cancer Research Institute, Kinderspitalgasse 9, A1190 Vienna, Austria.
Siligan
Christine
C
Kreppel
Michael
M
Aryee
Dave
D
Kovar
Heinrich
H
D001859:Bone Neoplasms / Q000235:genetics / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics* / Q000502:physiology*; D034802:RNA-Binding Protein EWS / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000235:genetics / Q000503:physiopathology*; D014178:Translocation, Genetic
C106031:EWS-FLI fusion protein; C078433:FLI1 protein, human; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS