The ETS transcription factor ETV6 constrains the transcriptional activity of EWS-FLI to promote Ewing sarcoma.

Transcription factors (TFs) are frequently mutated in cancer. Paediatric cancers exhibit few mutations genome-wide but frequently harbour sentinel mutations that affect TFs, which provides a context to precisely study the transcriptional circuits that support mutant TF-driven oncogenesis. A broadly relevant mechanism that has garnered intense focus involves the ability of mutant TFs to hijack wild-type lineage-specific TFs in self-reinforcing transcriptional circuits. However, it is not known whether this specific type of circuitry is equally crucial in all mutant TF-driven cancers. Here we describe an alternative yet central transcriptional mechanism that promotes Ewing sarcoma, wherein constraint, rather than reinforcement, of the activity of the fusion TF EWS-FLI supports cancer growth. We discover that ETV6 is a crucial TF dependency that is specific to this disease because it, counter-intuitively, represses the transcriptional output of EWS-FLI. This work discovers a previously undescribed transcriptional mechanism that promotes cancer. © 2023. The Author(s).

Citation

Diana Y Lu, Jana M Ellegast, Kenneth N Ross, Clare F Malone, Shan Lin, Nathaniel W Mabe, Neekesh V Dharia, Ashleigh Meyer, Amy Conway, Angela H Su, Julia Selich-Anderson, Cenny Taslim, Andrea K Byrum, Bo Kyung A Seong, Biniam Adane, Nathanael S Gray, Miguel N Rivera, Stephen L Lessnick, Kimberly Stegmaier. The ETS transcription factor ETV6 constrains the transcriptional activity of EWS-FLI to promote Ewing sarcoma. Nature cell biology. 2023 Feb;25(2):285-297

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PMID: 36658220

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