KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition
KDM6 demethylases integrate DNA repair gene regulation and loss of KDM6A sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition
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DOI：
10.1038/s41375-023-01833-z
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发表时间：
2023-01-31
期刊：
影响因子：
11.4
通讯作者：
Sengupta, Amitava
中科院分区：
文献类型：
--
作者：
Boila, Liberalis Debraj;Ghosh, Subhadeep;Sengupta, Amitava
急性髓系白血病 (AML) 是一种异质性、侵袭性恶性肿瘤，预后不佳，且靶向治疗的可用性有限。表观遗传失调导致 AML 发病机制。 KDM6 蛋白是组蛋白 3-赖氨酸-27-去甲基酶，在 AML 中发挥上下文依赖性作用。我们发现 KDM6 去甲基酶功能关键性地调节 AML 中的 DNA 损伤修复 (DDR) 基因表达。从机制上讲，KDM6 表达受基因毒性应激调节，KDM6A-(UTX) 和 KDM6B-(JMJD3) 缺陷会损害 DDR 转录激活并损害修复潜力。尽管很大一部分复发性 AML 的 KDM6A 表达上调，但获得性 KDM6A 功能丧失突变与化疗耐药有关。奥拉帕尼治疗减少了 KDM6A 突变 AML 患者来源的异种移植物的植入，突出了使用聚（ADP-核糖）聚合酶（PARP）抑制的合成致死性。至关重要的是，较高的 KDM6A 表达与 Venetoclax 耐受性相关。 KDM6A 的缺失会增加线粒体活性、BCL2 表达，并使 AML 细胞对维奈托克敏感。此外，BCL2A1 与 Venetoclax 耐药相关，KDM6A 缺失伴随着 BCL2A1 下调。证实了这些结果，在诱导 AML 细胞凋亡方面，PARP 和 BCL2 双重靶向优于 PARP 或 BCL2 抑制剂单一疗法，并且携带 KDM6A 结构域突变的原代 AML 细胞对联合疗法更加敏感。总之，我们的研究阐明了支持基于亚型异质性的 AML 新型联合疗法的机制原理，并将 KDM6A 确立为确定治疗效果的分子调节剂。
Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. Epigenetic deregulation contributes to AML pathogenesis. KDM6 proteins are histone-3-lysine-27-demethylases that play context-dependent roles in AML. We inform that KDM6-demethylase function critically regulates DNA-damage-repair-(DDR) gene expression in AML. Mechanistically, KDM6 expression is regulated by genotoxic stress, with deficiency of KDM6A-(UTX) and KDM6B-(JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations are implicated in chemoresistance, although a significant percentage of relapsed-AML has upregulated KDM6A. Olaparib treatment reduced engraftment of KDM6A-mutant-AML-patient-derived xenografts, highlighting synthetic lethality using Poly-(ADP-ribose)-polymerase-(PARP)-inhibition. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, BCL2A1 associates with venetoclax resistance, and KDM6A loss was accompanied with a downregulated BCL2A1. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support of a novel combination therapy for AML based on subtype-heterogeneity, and establishes KDM6A as a molecular regulator for determining therapeutic efficacy.