ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

Jie Li, Phillip M. Galbo, Weida Gong, Aaron J. Storey, Yi-Hsuan Tsai, Xufen Yu, Jeong Hyun Ahn, Yiran Guo, Samuel G. Mackintosh, Ricky D. Edmondson, Stephanie D. Byrum, Jason E. Farrar, Shenghui He, Ling Cai, Jian Jin, Alan J. Tackett, Deyou Zheng and Gang Greg Wang ()
Additional contact information
Jie Li: University of North Carolina at Chapel Hill School of Medicine
Phillip M. Galbo: Albert Einstein College of Medicine
Weida Gong: University of North Carolina at Chapel Hill School of Medicine
Aaron J. Storey: University of Arkansas for Medical Sciences
Yi-Hsuan Tsai: University of North Carolina at Chapel Hill School of Medicine
Xufen Yu: Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Jeong Hyun Ahn: University of North Carolina at Chapel Hill School of Medicine
Yiran Guo: University of North Carolina at Chapel Hill School of Medicine
Samuel G. Mackintosh: University of Arkansas for Medical Sciences
Ricky D. Edmondson: University of Arkansas for Medical Sciences
Stephanie D. Byrum: University of Arkansas for Medical Sciences
Jason E. Farrar: Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute
Shenghui He: University of North Carolina at Chapel Hill School of Medicine
Ling Cai: University of North Carolina at Chapel Hill School of Medicine
Jian Jin: Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Alan J. Tackett: University of Arkansas for Medical Sciences
Deyou Zheng: Albert Einstein College of Medicine
Gang Greg Wang: University of North Carolina at Chapel Hill School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

Date: 2021
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DOI: 10.1038/s41467-021-21357-3

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