Progress in the molecular biology of ewing tumors.

Purpose/results/discussion. Rearrangement of the EWS gene with an ETS oncogene by chromosomal translocation is a hallmark of the Ewing family of tumors (EFT). Detectability, incidence, tumor specificity and variability of this aberration have been matters of intense investigation in recent years. A number of related alterations have also been found in other malignancies. The common consequence of these gene rearrangements is the generation of an aberrant transcription factor. In EFT, the ETS partner is responsible for target recognition. However, synergistic and possibly tissue-restricted transcription factors interacting with either the EWS or the ETS portion may influence target selection. Minimal domains of both fusion partners were defined that have proved necessary for the in vitro transformation of murine fibroblasts. These functional studies suggest a role for aberrant transcriptional regulation of transforming target genes by the chimeric transcription factors. Also, fusion of the two unrelated protein domains may affect overall protein conformation and consequently DNA binding specificity. Recent evidence suggests that EWS, when fused to a transcription factor, interacts with different partners than germ-line EWS. Variability in EWS-ETS gene fusions has recently been demonstrated to correlate with clinical outcome. This finding may reflect functional differences of the individual chimeric transcription factors. Alternatively, type and availability of specific recombinases at different time-points of stem cell development or in different stem cell lineages may determine fusion type. Studies on EFT cell lines using EWS-ETS antagonists do suggest a rate-limiting essential role for the gene rearrangement in the self-renewal capacity of EFT cells. The presence of additional aberrations varying in number and type that may account for immortalization and full transformation is postulated. Knowledge about such secondary alterations may provide valuable prognostic markers that could be used for treatment stratification.