Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Nat Commun. 2021 Feb 16;12(1):1045. doi: 10.1038/s41467-021-21357-3.
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.
在人类急性髓系白血病 (AML) 患者中存在着一种复发性染色体易位 t(10;17)(p15;q21)，该易位导致了一个异常的融合基因，称为 ZMYND11-MBTD1（ZM）；然而，其功能仍未确定。在这里，我们展示了 ZM 赋予了原始的小鼠造血干/祖细胞无限的自我更新能力，并在体内引起了 AML。基因组分析表明，ZM 直接结合并维持包括 Hoxa、Meis1、Myb、Myc 和 Sox4 在内的促白血病基因的高表达。在机制上，ZM 招募了 NuA4/Tip60 组蛋白乙酰转移酶复合物到顺式调控元件上，维持了富含组蛋白乙酰化和缺乏抑制性组蛋白标记的活跃染色质状态。ZM 的系统诱变表明，Tip60 相互作用和一个 H3K36me3 结合的 PWWP（Pro-Trp-Trp-Pro）结构域对于致癌作用是必不可少的。组蛋白乙酰化“读取”溴结构域蛋白抑制剂，作为 ZM 的下游因子，在治疗 ZM 诱导的 AML 中是有效的。总的来说，这项研究证明了 ZM 对 AML 的致病作用，研究了它的基因调控作用，并报告了一种有吸引力的基于机制的治疗策略。
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