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

摘要: The Ewing sarcoma family of tumors expresses aberrant EWSR1- (EWS) fusion genes that are derived from chromosomal translocation. Although these well characterized as transcription factors, their formation leaves a single EWS allele in the cells and contribution loss makes towards disease pathogenesis is unknown. To address this question, we utilized zebrafish mutants for ewsa tp53. tp53(M214K)w/m line ewsaw/m, zygotic ewsam/m Maternal-Zygotic (MZ) lines all displayed zero to low incidence tumorigenesis. However, when tp53 mutant were crossed with each other, tumorigenesis drastically increased. Furthermore, 27 hour post fertilization (hpf) MZ embryos higher chromosome numbers mitotic dysfunction compared wildtype embryos. Consistent finding, tumor samples obtained ewsam/m;tp53w/m heterozygosity (LOH) locus. These results suggest Ewsa inhibits LOH induction, possibly by maintaining stability. We propose promotes deficiency may contribute EWS-fusion-expressing sarcomas.