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

Cao, Zhendong, Budinich, Krista A, Huang, Hua, Ren, Diqiu, Lu, Bin, Zhang, Zhen, Chen, Qingzhou, Zhou, Yeqiao, Huang, Yu-Han, Alikarami‬, Fatemeh, Kingsley, Molly C, Lenard, Alexandra K, Wakabayashi, Aoi, Khandros, Eugene, Bailis, Will, Qi, Jun, Carroll, Martin P, Blobel, Gerd A, Faryabi, Robert B, Bernt, Kathrin M, Berger, Shelley L, Shi, Junwei (August 2021) ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency. Molecular Cell. ISSN 1097-2765

URL: https://pubmed.ncbi.nlm.nih.gov/34358447/
DOI: 10.1016/j.molcel.2021.07.018

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.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > epigenetics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > epigenetics
diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:
Communities: CSHL labs > Vakoc lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 5 August 2021
Date Deposited: 11 Aug 2021 13:28
Last Modified: 08 Sep 2021 13:31
URI: https://repository.cshl.edu/id/eprint/40316

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