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.