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Cancer Cell. 2018 Jan 8;33(1):13-28.e8. doi: 10.1016/j.ccell.2017.12.002.

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

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Molecular and Cellular Biology Program, Stony Brook University, New York, NY 11794, USA.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
3
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
ULAM/Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
5
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu.

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.

KEYWORDS:

MYB; SAGA; TAF12; TFIID; acute myeloid leukemia; coactivator; epigenetics

PMID:
29316427
PMCID:
PMC5764110
[Available on 2019-01-08]
DOI:
10.1016/j.ccell.2017.12.002
[Indexed for MEDLINE]

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