期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-021-21357-3
关键词
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资金
- UNC Lineberger Comprehensive Cancer Center Core Support Grant [P30-CA016086]
- NIH SIG grant [1S10OD025132-01A1]
- NIH IDeA National Resource for Quantitative Proteomics [TL1TR003109, P20GM121293, R24GM137786, S10OD018445, R01CA236209]
- NIH [R01-CA215284, R01-CA211336, R01GM122749]
- Concern Foundation for Cancer Research
- Gabrielle's Angel Foundation for Cancer Research
- Gilead Sciences Research Scholars Program in hematology/oncology
- When Everyone Survives (WES) Leukemia Research Foundation
This study reveals that the fusion gene ZMYND11-MBTD1 (ZM) induces AML in a subset of patients by activating the NuA4/TIP60 histone acetyltransferase complex. ZM directly regulates the expression of pro-leukemic genes, promoting the development of AML through sustaining an active chromatin state.
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.
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