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- Title
ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism.
- Authors
Li, Jie; Galbo, Phillip M.; Gong, Weida; Storey, Aaron J.; Tsai, Yi-Hsuan; Yu, Xufen; Ahn, Jeong Hyun; Guo, Yiran; Mackintosh, Samuel G.; Edmondson, Ricky D.; Byrum, Stephanie D.; Farrar, Jason E.; He, Shenghui; Cai, Ling; Jin, Jian; Tackett, Alan J.; Zheng, Deyou; Wang, Gang Greg
- 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. The fusion gene ZMYND11-MBTD1 (ZM) is present in a subgroup of patients with acute myeloid leukaemia (AML). Here, the authors show that ZM expression induces AML in a murine model though activating the NuA4/TIP60 histone acetyltransferase complex.
- Subjects
ACETYLTRANSFERASES; HISTONE acetyltransferase; ACUTE myeloid leukemia; CHROMATIN; CHROMOSOMAL translocation; HISTONES
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-21357-3