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NATURE CELL BIOLOGY
Volume -, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41556-022-01059-8
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Transcription factors (TFs) are often mutated in cancer, but pediatric cancers exhibit few genome-wide mutations yet frequently have sentinel mutations affecting TFs. This study describes an alternative, central transcriptional mechanism in Ewing sarcoma wherein the constraint of the fusion TF EWS-FLI's activity supports cancer growth. ETV6 is identified as a crucial TF in this disease, repressing the transcriptional output of EWS-FLI.
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. Independent but complementary studies from Vakoc and Stegmaier identify and characterize a role for ETV6 in counteracting the transcriptional activity of EWS-FLI during Ewing sarcoma development, which may be targeted for therapeutic benefits.
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