EWSR1-FLI1
Ewing’s sarcoma family tumors are a good example of how genome research has advanced our understanding of the molecular pathogenesis of an otherwise enigmatic disease.
This group of embryonal bone tumors is characterized by the expression of a chimeric ETS-family oncogene, predominantly EWS/FLI1.
There is now convincing evidence for a mesenchymal descent from an early pluripotent progenitor.
EWS/FLI1 has been shown to drive proliferation of Ewing’s sarcoma cells and block most of the differentiation potential except for a partial neural gene expression program.
The EWS/FLI1 fusion protein acts mainly as a gene activator, directly interacting with chromatin at two kinds of binding site: distant enhancers enriched in GGAA microsatellites, and proximal promoters containing classical ETS-binding motifs and recognition motifs for other transcription factors.
EWS/FLI1 also represses a large number of genes, mainly indirectly, presumably by altering microRNA expression and epigenetic mechanisms, and potentially affecting post-transcriptional gene regulation.
Modulation of EWS/FLI1 expression is not only a desirable therapeutic goal, but may also occur under physiological conditions and influence the course of the disease.
Pathology
EWS-FLI1 fusion gene in Ewing sarcoma/peripheral primitive neuroectodermal tumors
EWS-FLI1 fusion gene in one case of solid pseudopapillary tumor of the pancreas (#11000339#)
Biology
Ewing tumor fusion proteins block the differentiation of pluripotent marrow stromal cells (#12839926#)
EWS-FLI-1 fusion gene switches the differentiation program of neuroblastomas to Ewing sarcoma/peripheral primitive neuroectodermal tumors (#14973077#)
Identification of an Inhibitor of the EWS-FLI1 Oncogenic Transcription Factor by High-Throughput Screening. (#21653923#)
References
Downstream EWS/FLI1 - Upstream Ewing’s sarcoma. Kovar H. Genome Med. 2010 Jan 28;2(1):8. PMID: #20156317#
Identification of an Inhibitor of the EWS-FLI1 Oncogenic Transcription Factor by High-Throughput Screening. Grohar PJ, Woldemichael GM, Griffin LB, Mendoza A, Chen QR, Yeung C, Currier DG, Davis S, Khanna C, Khan J, McMahon JB, Helman LJ. J Natl Cancer Inst. 2011 Jun 8. PMID: #21653923#
Uren A, Toretsky JA. Ewing’s sarcoma oncoprotein EWS-FLI1: the perfect target without a therapeutic agent. Future Oncol. 2005 Aug;1(4):521-8. PMID: #16556028#
Rorie CJ, Thomas VD, Chen P, Pierce HH, O’Bryan JP, Weissman BE. The Ews/Fli-1 fusion gene switches the differentiation program of neuroblastomas to Ewing sarcoma/peripheral primitive neuroectodermal tumors. Cancer Res. 2004 Feb 15;64(4):1266-77. PMID: #14973077#
Hahm KB, Cho K, Lee C, Im YH, Chang J, Choi SG, Sorensen PH, Thiele CJ, Kim SJ. Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein. Nat Genet. 1999 Oct;23(2):222-7. PMID: #10508522#
Lessnick SL, Braun BS, Denny CT, May WA. Multiple domains mediate transformation by the Ewing’s sarcoma EWS/FLI-1 fusion gene. Oncogene. 1995 Feb 2;10(3):423-31. PMID: #7845667#
Ohno T, Rao VN, Reddy ES. EWS/Fli-1 chimeric protein is a transcriptional activator. Cancer Res. 1993 Dec 15;53(24):5859-63. PMID: #7503813#