Ewing sarcoma breakpoint region 1-Friend leukemia integration 1 transcription factor (EWS-FLI1) (EWS-FLI1)

EWS-FLI1 is a chimeric transcription factor resulting from the t(11;22)(q24;q12) chromosomal translocation, which is the hallmark genetic driver of Ewing sarcoma (PMID: 8036086). This fusion protein combines the potent transactivation domain of EWSR1 with the DNA-binding domain of the ETS-family transcription factor FLI1 (PMID: 16530701). It functions as a master regulator by binding to both high-affinity ETS sites and GGAA-microsatellite response elements, leading to the creation of neo-enhancers and the widespread dysregulation of gene expression (PMID: 25151357). EWS-FLI1 promotes oncogenesis by activating pathways involved in cell proliferation and survival while simultaneously repressing genes required for normal cellular differentiation (PMID: 22307178). Although traditionally considered "undruggable" due to its disordered structure, therapeutic efforts now focus on small molecules like TK216 that disrupt its interaction with essential co-factors like RNA helicase A (DHX9) or target its downstream epigenetic dependencies (PMID: 27413065).

Other names

EWSR1-FLI1EWS-FLI1 fusion proteint(11;22) translocation productEwing sarcoma fusion protein

Direct disruption of the protein-protein interaction between EWS-FLI1 and RNA helicase A (DHX9), redistribution of the fusion protein from its genomic binding sites, or inhibition of downstream epigenetic co-factors like LSD1 to reverse the oncogenic transcriptional program (PMID: 27413065, 31064780).