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 ewsaw/m, zygotic ewsam/m, and Maternal-Zygotic (MZ) ewsam/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 ewsam/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 ewsam/m;tp53w/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.
Highlights
EWS (Ewing sarcoma region 1, EWSR1) was originally identified as part of a fusion gene with FLI1, in Ewing sarcoma cells[1]
We discovered that the zebrafish ewsa mutant promotes tumorigenesis in the tp53w/m background by promoting loss of heterozygosity (LOH) of the wildtype tp[53] locus, suggesting that Ewsa acts to suppress tumorigenesis
EWS has an important role in regulating the cell cycle, and EWS-fusions in EWS-associated sarcomas result in the loss of one or both alleles of the gene, the contribution that this loss has on tumorigenesis is unknown
Summary
EWS (Ewing sarcoma region 1, EWSR1) was originally identified as part of a fusion gene with FLI1, in Ewing sarcoma cells[1]. Subsequent studies have shown that 90% of Ewing sarcoma tumors express the EWS/FLI1 fusion gene; the remainder express EWS-fusions with other ETS transcription factors: ERG, ETV1, ETV4, and FEV2,3. EWS is a multifunctional protein that regulates transcription and splicing, and as a result, it affects numerous biological processes, including cell differentiation. An example of this is the role EWS plays in the differentiation of brown adipocytes, through activation of BMP7 transcription[9]. We utilized a zebrafish ewsa loss of function mutant to analyze the effect that ewsa mutation has on tumorigenesis. The zebrafish tp53(M214K) mutant, a well characterized cancer model, was utilized as a platform for studying tumor promotion. We propose a novel mechanism: loss of EWS contributes to pathogenesis in sarcomas expressing EWS-fusion genes
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