ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency.

Abstract

The transformed state in acute leukemia requires gene regulatory programs involving transcription factors and chromatin modulators. Here, we uncover an IRF8-MEF2D transcriptional circuit as an acute myeloid leukemia (AML)-biased dependency. We discover and characterize the mechanism by which the chromatin "reader" ZMYND8 directly activates IRF8 in parallel with the MYC proto-oncogene through their lineage-specific enhancers. ZMYND8 is essential for AML proliferation in vitro and in vivo and associates with MYC and IRF8 enhancer elements that we define in cell lines and in patient samples. ZMYND8 occupancy at IRF8 and MYC enhancers requires BRD4, a transcription coactivator also necessary for AML proliferation. We show that ZMYND8 binds to the ET domain of BRD4 via its chromatin reader cassette, which in turn is required for proper chromatin occupancy and maintenance of leukemic growth in vivo. Our results rationalize ZMYND8 as a potential therapeutic target for modulating essential transcriptional programs in AML.

• Authors: Zhendong Cao, Krista A Budinich, Hua Huang, Diqiu Ren, Bin Lu, Zhen Zhang, Qingzhou Chen, Yeqiao Zhou, Yu-Han Huang, Fatemeh Alikarami, Molly C Kingsley, Alexandra K Lenard, Aoi Wakabayashi, Eugene Khandros, Will Bailis, Jun Qi, Martin P Carroll, Gerd A Blobel, Robert B Faryabi, Kathrin M Bernt, Shelley L Berger, Junwei Shi
• Journal: Molecular cell (Mol Cell) Vol. 81 Issue 17 Pg. 3604-3622.e10 (09 02 2021) ISSN: 1097-4164 [Electronic] United States
• PMID: 34358447 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Cell Cycle Proteins
• Chromatin
• Interferon Regulatory Factors
• MAS1 protein, human
• Nuclear Proteins
• Proto-Oncogene Mas
• Transcription Factors
• Tumor Suppressor Proteins
• ZMYND8 protein, human
• interferon regulatory factor-8

Topics

• Cell Cycle Proteins (metabolism)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Chromatin (genetics)
• Enhancer Elements, Genetic (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Interferon Regulatory Factors (genetics, metabolism)
• Leukemia, Myeloid, Acute (genetics, metabolism)
• Nuclear Proteins (metabolism)
• Promoter Regions, Genetic (genetics)
• Proto-Oncogene Mas
• Transcription Factors (metabolism)
• Transcription, Genetic (genetics)
• Tumor Suppressor Proteins (genetics, metabolism)