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

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
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > epigenetics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > epigenetics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
diseases & disorders > cancer > cancer types > leukemia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogenes
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression > promoter
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > suppressor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
diseases & disorders > cancer > cancer types
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: 23 Jan 2024 18:59
PMCID: PMC8932643
URI: https://repository.cshl.edu/id/eprint/40316

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