Chromosome Translocation-Mediated Conversion of a Tumor Suppressor Gene into a Dominant Oncogene: Fusion of EWS1 to WT1 in Desmoplastic Small Round Cell Tumors

Abstract

The preceding articles in this volume have provided a unique overview of genetic and biochemical mechanisms which underlie oncogenic conversion of transcription factor function. As is evident, many of the models have derived from the study of pediatric and adult leukemias. These studies have provided a paradigm for the emerging analyses of chromosomal translocations involving transcription factors in solid tumors. This is exemplified by the manuscript of Barr who examines the PAX3-FKHR fusion transcription factor whose mechanism likely involves increased activation of normal PAX3 target genes. A similar but probably not identical mechanistic theme is echoed by the EWS and TLS fusions described by Ron and May. Like PAX3-FKHR, the EWS/TLS fusions confer a novel activation domain to an otherwise unaltered DNA binding domain, thereby creating a dominant oncogene. Most remarkable is the diversity of DNA-binding domain types which are involved in EWS/TLS fusions and, concomitantly, the diversity of the disease processes initiated. This article will expand on this theme by describing a new member of the EWS/TLS family of oncogenes, namely EWS-WT1, which occurs in the solid tumor desmoplastic small round cell sarcoma (DSRCT). The EWS-WT1 fusion is unique in that its DNA binding domain is derived from the Wilms’ tumor-1 (WT1) tumor suppressor protein. This is one of the first examples of chromosomal-translocation-mediated fusion of a proto-oncogene (EWS) and a tumor suppressor gene (WT1) which creates a dominant oncogene. In order to understand the context of these findings, we will first provide brief reviews of the biology and genetics of WT1, EWS, and DSRCT.