ArticleProceedings of the National Academy of Sciences of the United States of America2026
STAG2 loss amplifies EWS-FLI1-driven microsatellite enhancer activity promoting Ewing sarcoma aggressiveness.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Ewing sarcoma is driven by chromosomal translocations that fuse a FET RNA-binding protein to an ETS transcription factor, most commonly generating the EWS-FLI1 fusion oncoprotein. EWS-FLI1 engages GGAA microsatellite repeats to form de novo enhancers that activate oncogenic transcriptional programs essential for tumorigenesis. In addition to this truncal driver, recurrent loss-of-function alterations in the cohesin subunit STAG2 occur in approximately 10 to 15% of Ewing sarcomas and are associated with adverse clinical outcomes. However, how STAG2 loss reshapes EWS-FLI1 chromatin engagement and transcriptional output remains poorly understood. Here, using genetic STAG2 loss-of-function models combined with integrative multiomic profiling, we demonstrate that STAG2-cohesin deficiency reprograms the EWS-FLI1 chromatin landscape by altering its binding at GGAA-microsatellite enhancers. Despite increased EWS-FLI1 protein abundance, STAG2 loss eliminates over 40% of EWS-FLI1 binding sites, predominantly at enhancers containing short (1-4) GGAA repeats, while concurrently increasing binding at multimeric enhancers with ≥5 GGAA-repeat motifs. These reprogrammed sites show changes in both chromatin accessibility and H3K27ac, leading to selective amplification of EWS-FLI1 activity at multimeric microsatellite enhancers. By integrating Hi-C chromatin interaction maps with altered EWS-FLI1 occupancy, we define distinct monomeric and multimeric GGAA enhancer-driven transcriptional gene signatures and demonstrate that STAG2 loss selectively augments the multimeric transcriptional program. Consistently, the long GGAA microsatellite-activated gene signature is enriched in patient tumors with aggressive clinical features and deleterious STAG2 alterations. Together, these findings reveal that STAG2 loss reprograms, rather than globally attenuates, EWS-FLI1 function, amplifying a high-risk oncogenic transcriptional state in Ewing sarcoma.
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