A new view of Ewing's sarcoma : testing the provocative hypothesis that post-transcriptional mechanisms of mRNA processing contribute to the oncogenic properties of EWS-Fli1 fusion.

The FET/TET proteins, which include TLS/FUS, EWS, and TAF15 are RNA- and DNA-binding proteins, with proposed functions in transcription and RNA processing. The family is notorious because it is involved in chromosomal translocations in which the 5' part of human FET genes is fused to the 3' region of genes encoding potent transcription factors, including members of the Erg transcription factor family (ERG, Fli1 and FEV). FET-Erg fusions have been associated with Ewing's sarcoma (ES) family tumors and acute myeloid leukemia and a plethora of evidence leaves little doubt that these fusions are essential to the development of these malignancies. Despite their importance, our knowledge on how FET-Erg oncogenic fusions impact on tumor biology remains incomplete. Because they include the C-terminal half of Erg proteins, which contains the ETS DNA-binding domain, fused to the amino-terminal portion of FET proteins, which behaves as a potent transcription activation domain, FET-Erg fusions have mostly been studied as oncogenic transcription factors. The current model suggests that FET-Erg fusions aberrantly regulate the transcription of genes that promote the establishment and/or the maintenance of the malignant phenotype. Despite years of investigations and identification of multiple transcriptional targets, this model has failed to fully decipher the oncogenic potential of FET-Erg fusions. In this project, we would like to take advantage of recent findings from our laboratories and assess the provocative hypothesis that important post-transcriptional functions of FET and Erg proteins, in particular in mRNA degradation and translation might be deregulated in FET-Erg fusions and contribute to their roles in cancer initiation and progression. We believe that a full understanding of oncogenic FET-Erg proteins functions can only arise from integrating their transcriptional and post-transcriptional functions. We are also convinced that this new perspective on FET-Erg fusions will provide novel therapeutic opportunities for ES and various FET-Erg-related cancers.