title: Loss of Ewing sarcoma EWS allele promotes tumorigenesis by inducing chromosomal instability in zebrafish.
abstract: 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.
authors.affiliation: University of Kansas, Molecular Biosciences, Haworth Rm7031, 1200 Sunnyside Avenue, Lawrence KS 66045, USA.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Park
authors.affiliation: Lawrence Memorial Hospital, Department of Pathology, 325 Maine St, Lawrence KS 66044, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Galbraith
authors.affiliation: Lawrence Memorial Hospital, Department of Pathology, 325 Maine St, Lawrence KS 66044, USA.
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Turner
authors.affiliation: University of Kansas, Molecular Biosciences, Haworth Rm7031, 1200 Sunnyside Avenue, Lawrence KS 66045, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Mehojah
authors.affiliation: University of Kansas, Molecular Biosciences, Haworth Rm7031, 1200 Sunnyside Avenue, Lawrence KS 66045, USA.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Azuma
mesh_terms: D000483:Alleles; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D034802:RNA-Binding Protein EWS / Q000235:genetics / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D034802:RNA-Binding Protein EWS; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins