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The Ewing sarcoma family of tumors expresses aberrant  EWSR1- (EWS)  fusion genes that are derived from chromosomal translocation. Although these fusion genes are well characterized as transcription factors, their formation leaves a single  EWS  allele in the sarcoma cells, and the contribution that the loss of  EWS  makes towards disease pathogenesis is unknown. To address this question, we utilized zebrafish mutants for  ewsa  and  tp53 . The zebrafish  tp53(M214K)   w / m   line and the  ewsa   w / m  , zygotic  ewsa   m / m  , and Maternal-Zygotic (MZ)  ewsa   m / m   lines all displayed zero to low incidence of tumorigenesis. However, when the  ewsa  and  tp53  mutant lines were crossed with each other, the incidence of tumorigenesis drastically increased. Furthermore, 27 hour post fertilization (hpf) MZ  ewsa   m / m   mutant embryos displayed a higher incidence of aberrant chromosome numbers and mitotic dysfunction compared to wildtype zebrafish embryos. Consistent with this finding, tumor samples obtained from  ewsa   m / m  ; tp53   w / m   zebrafish displayed loss of heterozygosity (LOH) for the wildtype  tp53  locus. These results suggest that wildtype Ewsa inhibits LOH induction, possibly by maintaining chromosomal stability. We propose that the loss of  ewsa  promotes tumorigenesis, and  EWS  deficiency may contribute to the pathogenesis of  EWS -fusion-expressing sarcomas.

Loss of Ewing sarcoma EWS allele promotes tumorigenesis by inducing chromosomal instability in zebrafish