ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism
Open Access
- 16 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 12 (1), 1-18
- https://doi.org/10.1038/s41467-021-21357-3
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.Funding Information
- Gabrielle's Angel Foundation for Cancer Research
- Gilead Sciences
- grants of a Concern Foundation for Cancer Research grant (to G.G.W.), When Everyone Survives (WES) Leukemia Research Foundation (to G.G.W.).
This publication has 83 references indexed in Scilit:
- An H3K36 Methylation-Engaging Tudor Motif of Polycomb-like Proteins Mediates PRC2 Complex TargetingMolecular Cell, 2013
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylationNature Structural & Molecular Biology, 2012
- Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemiaNature, 2011
- Histone Methylation by PRC2 Is Inhibited by Active Chromatin MarksMolecular Cell, 2011
- Fast and accurate long-read alignment with Burrows–Wheeler transformBioinformatics, 2010
- Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD fingerNature, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- The Immunological Genome Project: networks of gene expression in immune cellsNature Immunology, 2008
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005