Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.
Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Human Biology and BioImaging, LMU Munich, Planegg Martinsried, Germany.
Sci Rep. 2021 Mar 12;11(1):5838. doi: 10.1038/s41598-021-84708-6.
Chemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms inducing resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicate that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.
化疗耐药性是急性髓系白血病（AML）治疗的主要障碍。尽管取得了快速进展，但诱导耐药性发展的各种机制仍有待详细定义。在这里，我们报告组蛋白甲基转移酶 EZH2 的功能丧失突变（LOF）有可能赋予对化疗药物阿糖胞苷的耐药性。我们确定了七个不同的 EZH2 突变，这些突变通过多种机制导致 H3K27 三甲基化的丧失。对匹配的诊断和复发样本的分析显示 EZH2 的异质性调节和 50%的患者中 EZH2 的丢失。我们证实 EZH2 的缺失在细胞系 HEK293T 和 K562 以及患者来源的异种移植模型中诱导了对阿糖胞苷的耐药性。蛋白质组学和转录组学分析表明，耐药性是通过上调多个直接和间接的 EZH2 靶基因赋予的，这些基因参与细胞凋亡逃逸、增殖增强和跨膜转运蛋白功能改变。我们的数据表明，EZH2 的缺失导致其靶基因的上调，为细胞提供了选择性生长优势，从而介导化疗耐药性。
