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A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis.

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.

Pubmed ID: 21979944 RIS Download

Mesh terms: Animals | Animals, Genetically Modified | Cell Transformation, Neoplastic | Disease Models, Animal | Embryo, Nonmammalian | Embryonic Development | Gene Expression Profiling | Gene Expression Regulation, Neoplastic | Humans | Neoplasm Transplantation | Oncogene Proteins, Fusion | Proto-Oncogene Protein c-fli-1 | RNA-Binding Protein EWS | Sarcoma, Ewing | Transgenes | Zebrafish

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA135731
  • Agency: NCI NIH HHS, Id: 1R01CA135731

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Database for Annotation Visualization and Integrated Discovery

A database which provides a comprehensive set of functional annotation tools for investigators to understand biological meaning behind large list of genes. For any given gene list, DAVID tools are able to perform a variety of actions such as identifying enriched biological themes (particularly GO terms), discovering enriched functional-related gene groups, clustering redundant annotation terms, and visualizing genes on BioCarta and KEGG pathway maps.

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WebGestalt: WEB-based GEne SeT AnaLysis Toolkit

A web-based gene set analysis toolkit designed for functional genomic, proteomic, and large-scale genetic studies from which large number of gene lists (e.g. differentially expressed gene sets, co-expressed gene sets etc) are continuously generated. WebGestalt incorporates information from different public resources and provides a way for biologists to make sense out of gene lists. This version of WebGestalt supports eight organisms, including human, mouse, rat, worm, fly, yeast, dog, and zebrafish.

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Broad Institute

A biomedical and genomic research center that is independently governed that encompasses three types of organizational units: core member laboratories, programs and platforms which work together and with other collaborators to tackle critical problems in human biology and disease. Data and cutting edge software tools are generated and developed, and these tools analyze those data (increasingly large genome-related datasets) which is shared openly with the scientific community. The Broad faculty includes core members and associate members. All associate members hold primary appointments in a home department at one of the partner institutions, but are deeply involved in the scientific work and culture of the Broad Institute. It is formally affiliated with the Massachusetts Institute of Technology, Harvard University and its affiliated hospitals.

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