Ewing sarcoma breakpoint region 1–Friend leukemia integration 1 fusion protein (EWS–FLI1)

The Ewing sarcoma breakpoint region 1–Friend leukemia integration 1 fusion protein (EWS–FLI1) is a chimeric transcription factor produced by the chromosomal translocation t(11;22)(q24;q12), which joins the N-terminal transactivation domain of EWSR1 to the C-terminal DNA-binding domain of FLI1, an ETS family transcription factor[1][3][4]. This fusion results in a potent oncoprotein present in over 85% of Ewing sarcoma cases, where it acts as a master regulator of aberrant gene expression and alternative splicing, driving tumorigenesis in pediatric and young adult bone and soft tissue[3][4][5][6]. EWS–FLI1 binds GGAA-microsatellite elements in DNA, forming nucleoprotein filaments that activate or repress target genes essential for tumor growth and progression, and also disturbs normal splicing machinery and DNA-damage response[1][2][3][5]. The protein is a key therapeutic target, though clinical development has been hindered by the technical challenges of targeting a non-enzymatic, intrinsically disordered, fusion-driven transcription factor[5][6]. The presence and variant type of the EWS–FLI1 fusion transcript serve as both a diagnostic and prognostic biomarker in Ewing sarcoma[4].

Other names

EWS–FLI1 fusion geneEWS/FLI1 fusion transcriptEWS::FLI1 fusion proteinEWS–FLI fusion transcript

Inhibition of EWS–FLI1 disrupts its protein–protein interaction network (e.g., with RNA helicase A and other spliceosome proteins), impeding its oncogenic transcriptional and splicing regulatory functions[2]. Targeting DNA binding or phase separation properties to inhibit EWS–FLI1–driven gene expression[3].