EWS-FLI1 and Ewing's sarcoma - Recent molecular data and new insights

The EWS-FLI1 fusion resulting from the specific t(11;22)(q24;q12) of Ewing's sarcoma was the first sarcoma gene fusion to be cloned, a decade ago. Moving from the cloning of this oncogenic chimeric transcription factor to the further elucidation of its pathogenetic mechanisms has revealed new complexities in the biology of this tumor which may be relevant to other fusion oncogenes as well. The present review highlights recent advances in three avenues of investigation that are providing new insights into this particular neoplasm and into the biology of EWS-FLI1 and related fusion proteins, namely the identification of various mitogenic targets of this aberrant transcription factor, its possible role as a deregulator of splicing, and the role of the p53 pathway in modulating its oncogenicity. The EWS-FLI1 fusion of Ewing's sarcoma was the first sarcoma gene fusion to be cloned, exactly 10 years ago.(1) Although this fusion and the many others subsequently cloned in other sarcomas have matured into widely accepted molecular diagnostic markers, hopes that they might lead to simple mechanistic explanations of how these sarcomas arise proved unrealistic. EWS-FLI1 has perhaps been emblematic of the difficulty in bridging this mechanistic gap between the cloning of a fusion oncogene and the further elucidation of the pathogenesis of the corresponding cancer. More general overviews of Ewing's sarcoma and the many other basic and applied studies of EWS-FLI1 are available elsewhere.(2-4) The aim of the present review is to highlight recent advances in three avenues of investigation that are providing new insights into this particular neoplasm and into the biology of EWS-FLI1 (and related fusion proteins).