Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599.
Proc Natl Acad Sci U S A. 2022 Mar 1;119(9). doi: 10.1073/pnas.2122940119.
Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or mixed lineage leukemia (MLL) rearrangement (MLL-r) share transcriptomic profiles associated with stemness-related gene signatures and display poor prognosis. The molecular underpinnings of AML aggressiveness and stemness remain far from clear. Studies with EZH2 enzymatic inhibitors show that polycomb repressive complex 2 (PRC2) is crucial for tumorigenicity in NUP98-NSD1 AML, whereas transcriptomic analysis reveal that , a lysine demethylase gene carrying "bivalent" chromatin domains, is directly repressed by PRC2. While ectopic expression of Kdm5b suppressed AML growth, its depletion not only promoted tumorigenicity but also attenuated anti-AML effects of PRC2 inhibitors, demonstrating a PRC2-| axis for AML oncogenesis. Integrated RNA sequencing (RNA-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq), and Cleavage Under Targets & Release Using Nuclease (CUT&RUN) profiling also showed that Kdm5b directly binds and represses AML stemness genes. The anti-AML effect of Kdm5b relies on its chromatin association and/or scaffold functions rather than its demethylase activity. Collectively, this study describes a molecular axis that involves histone modifiers (PRC2-|) for sustaining AML oncogenesis.
急性髓系白血病（AML）伴 NUP98-NSD1 或混合谱系白血病（MLL）重排（MLL-r）具有与干性相关基因特征相关的转录组谱，并显示预后不良。AML 侵袭性和干性的分子基础仍远未明确。对 EZH2 酶抑制剂的研究表明，多梳抑制复合物 2（PRC2）对于 NUP98-NSD1 AML 的致瘤性至关重要，而转录组分析显示，携带“二价”染色质结构域的赖氨酸去甲基化酶基因，直接受到 PRC2 的抑制。虽然 Kdm5b 的异位表达抑制了 AML 的生长，但它的耗竭不仅促进了肿瘤发生，而且减弱了 PRC2 抑制剂的抗 AML 作用，证明了 PRC2-|轴在 AML 癌发生中的作用。整合 RNA 测序（RNA-seq）、染色质免疫沉淀测序（ChIP-seq）和靶向核酶切割和释放（CUT&RUN）分析还表明，Kdm5b 直接结合并抑制 AML 干性基因。Kdm5b 的抗 AML 作用依赖于其染色质结合和/或支架功能，而不是其去甲基酶活性。总之，这项研究描述了一个涉及组蛋白修饰物（PRC2-|）的分子轴，用于维持 AML 癌发生。
