Abstract
SUMMARYEwing’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.
Highlights
Chromosomal translocations that create fusion oncogenes have long been recognized as a cause of human cancers such as leukemias and sarcomas (Mitelman et al, 2007), and recently have been described in prostate (Tomlins et al, 2005; Brenner and Chinnaiyan, 2009) and lung cancer (Soda et al, 2007)
To develop an animal model in which to study the function of EWS-FLI1, we created transgenic zebrafish carrying the human EWS-FLI1 fusion protein, using the Tol2 transposon system (Kawakami et al, 2004)
From over 300 wild-type embryos injected with the three different EWS-FLI1 transgenes and raised to adulthood, we identified two fish with tumors
Summary
Chromosomal translocations that create fusion oncogenes have long been recognized as a cause of human cancers such as leukemias and sarcomas (Mitelman et al, 2007), and recently have been described in prostate (Tomlins et al, 2005; Brenner and Chinnaiyan, 2009) and lung cancer (Soda et al, 2007). In Ewing’s sarcoma, a malignant bone tumor that most commonly occurs in adolescents and young adults, the discovery of a characteristic chromosomal translocation t(11;22)(q24;q12) (Delattre et al, 1992) marked a turning point in the understanding of the biology of the disease. In the majority of Ewing’s tumors, the N-terminal portion of EWS becomes fused to the C-terminal portion of FLI-1, which includes an ETS family DNA binding domain (Delattre et al, 1992). In some (~15%) Ewing’s tumors, alternative chromosomal translocations create fusions between EWS and other ETS family transcription factors. These alternative fusions suggest that EWS mediates a critical change in ETS family transcription factors that allows them
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
