# EWSR1-FLI1 fusion

Source: https://onco.cc/targets/ewsr1-fli1/  
OnCo record `ewsr1-fli1` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The fused gene that defines Ewing sarcoma: an aberrant transcription factor that has resisted 30 years of drug design.

## Summary

The t(11;22) fusion joins the low-complexity prion-like domain of EWSR1 to the DNA-binding domain of FLI1, creating a neomorphic transcription factor that binds GGAA microsatellites, opens chromatin (with BAF complex) and reprograms the cell. It is present in ~85% of Ewing sarcoma (EWSR1-ERG in most of the rest) and is the sole recurrent driver. Direct inhibition attempts (TK216/mithramycin analogues, YK-4-279) failed clinically; indirect strategies target its dependencies: LSD1 (seclidemstat), PARP/DNA damage response (trabectedin, lurbinectedin, PARP inhibitors), cell-cycle (CDK4/6, WEE1), IGF-1R (antibodies failed), and degraders. Detection by FISH/RT-PCR/RNA-seq is diagnostic; fusion ctDNA is an emerging MRD marker.

## Fields

- Kind: Target
- Last checked: 2026-09-08
- Tags: gap-fill
- Symbol: EWSR1::FLI1
- Class: transcription
- Biology: EWSR1-FLI1 is a fusion oncoprotein; the EWSR1 domain drives phase separation and recruits BAF, while the FLI1 ETS domain binds GGAA repeats to activate (e.g. NR0B1, NKX2-2) and, at canonical ETS sites, repress (e.g. TGFBR2, IGFBP3) target genes.
- Where found: Ewing sarcoma (~85%); EWSR1 fusions with other partners define desmoplastic small round cell tumour (EWSR1-WT1), clear cell sarcoma (EWSR1-ATF1), myxoid liposarcoma (FUS/EWSR1-DDIT3)

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/EWS/FLI
- Delattre 1992 (Nature): https://doi.org/10.1038/359162a0

## Connected records

- cancers: [Ewing sarcoma](https://onco.cc/cancers/ewing-sarcoma/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/)
- technologies: [Cytogenetics and FISH](https://onco.cc/technologies/cytogenetics-fish/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/), [RNA sequencing & expression profiling](https://onco.cc/technologies/rna-seq/)
- drugs: [Lurbinectedin](https://onco.cc/drugs/lurbinectedin/), [TK216](https://onco.cc/drugs/tk216/), [Trabectedin](https://onco.cc/drugs/trabectedin/)
- terms: [Cytogenetics and karyotype](https://onco.cc/terms/cytogenetics/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [Histological response to induction chemotherapy (osteosarcoma and Ewing sarcoma)](https://onco.cc/terms/histological-response-induction/)
- key papers: [Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours](https://onco.cc/key-papers/paper-delattre-nature/)
- pathways: [Drivers, passengers & the two-hit model](https://onco.cc/pathways/oncogene-activation-two-hit/), [Transcriptional machinery & addiction](https://onco.cc/pathways/transcription-addiction/)

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