Ewing’s sarcoma, a malignant bone tumor of children and young adults, is a member of the small-round-blue-cell tumor family.
Ewing’s sarcoma family tumors (ESFTs), which include peripheral primitive neuroectodermal tumors (PNETs), are characterized
by chromosomal translocations that generate fusions between the EWS gene and ETS-family transcription factors, most commonly FLI1. The EWS-FLI1 fusion oncoprotein represents an attractive therapeutic target for treatment of Ewing’s sarcoma. The cell of
origin of ESFT and the molecular mechanisms by which EWS-FLI1 mediates tumorigenesis remain unknown, and few animal models
of Ewing’s sarcoma exist. Here, we report the use of zebrafish as a vertebrate model of EWS-FLI1 function and tumorigenesis.
Mosaic expression of the human EWS-FLI1 fusion protein in zebrafish caused the development of tumors with histology strongly
resembling that of human Ewing’s sarcoma. The incidence of tumors increased in a p53 mutant background, suggesting that the
p53 pathway suppresses EWS-FLI1-driven tumorigenesis. Gene expression profiling of the zebrafish tumors defined a set of genes
that might be regulated by EWS-FLI1, including the zebrafish ortholog of a crucial EWS-FLI1 target gene in humans. Stable
zebrafish transgenic lines expressing EWS-FLI1 under the control of the heat-shock promoter exhibit altered embryonic development and defective convergence and extension,
suggesting that EWS-FLI1 interacts with conserved developmental pathways. These results indicate that functional targets of
EWS-FLI1 that mediate tumorigenesis are conserved from zebrafish to human and provide a novel context in which to study the
function of this fusion oncogene.