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A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia.

ABSTRACT: Targeting of general coactivators is an emerging strategy to interfere with oncogenic transcription factors (TFs). However, coactivator perturbations often lead to pleiotropic effects by influencing numerous TFs. Here we identify TAF12, a subunit of TFIID and SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a TF with established roles in leukemogenesis. Ectopic expression of the TAF4 histone-fold fragment can efficiently squelch TAF12 in cells, suppress MYB, and regress AML in mice. Our study reveals a strategy for potent MYB inhibition in AML and highlights how an oncogenic TF can be selectively neutralized by targeting a general coactivator complex.

SUBMITTER: Xu Y

PROVIDER: S-EPMC5764110 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia.

Xu Yali Y Milazzo Joseph P JP Somerville Tim D D TDD Tarumoto Yusuke Y Huang Yu-Han YH Ostrander Elizabeth L EL Wilkinson John E JE Challen Grant A GA Vakoc Christopher R CR

Cancer cell 20180101 1

Targeting of general coactivators is an emerging strategy to interfere with oncogenic transcription factors (TFs). However, coactivator perturbations often lead to pleiotropic effects by influencing numerous TFs. Here we identify TAF12, a subunit of TFIID and SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a T ...[more]

PMID: 29316427

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