急性髓系白血病（AML）是一种异质性、具有侵袭性和预后极差的恶性肿瘤，目前有限的靶向治疗手段。表观遗传调节异常对AML病理发生起贡献。KDM6蛋白是组蛋白3甲基-27-去甲基酶，对AML扮演着环境依赖的作用。我们的研究表明KDM6启动子控制DNA损伤修复（DDR）基因表达对AML至关重要。在分子机制上，KDM6表达受基因毒性应激控制，KDM6A（UTX）和KDM6B（JMJD3）的不足会损害DDR转录激活并妨碍修复潜力。获得性KDM6A失活突变与化疗耐药有关，虽然一个显著的比例复发AML表达上调KDM6A。奥拉帕尼治疗可减少KDM6A突变AML患者来源的异种移植，强调使用多聚（ADP核糖）聚合酶（PARP）抑制剂的合成致死作用。关键是，高表达KDM6A与维内托拉克斯的耐受性有关。KDM6A失活可增加线粒体活性，BCL2表达，并使AML细胞对维内托拉克斯更敏感。此外，BCL2A1与维内托拉克斯抗药性相关，KDM6A失活伴随BCL2A1下调。证实这些结果后，同时靶向PARP和BCL2比PARP或BCL2抑制剂单独治疗更优于诱导AML细胞凋亡，承载KDM6A区域突变的初级AML细胞甚至对该组合更敏感。因此，我们的研究阐述了一种基于亚型异质性的AML新型联合治疗的机制基础，并确定KDM6A是决定治疗效果的分子调节器。©2023作者，由施普林格自然出版集团有限公司独家许可。

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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.