Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair
Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair
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HDAC 和 MLL-menin 相互作用的共同抑制通过破坏 DNA 损伤检查点和 DNA 修复来靶向 MLL 重排的急性髓系白血病细胞
DOI：
10.1186/s13148-019-0723-0
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发表时间：
2019
影响因子：
5.7
通讯作者：
Xu Bing
中科院分区：
文献类型：
--
作者：
Ye Jing;Zha Jie;Shi Yuanfei;Li Yin;Yuan Delin;Chen Qinwei;Lin Fusheng;Fang Zhihong;Yu Yong;Dai Yun;Xu Bing
虽然混合系白血病（MLL）基因的异常易位驱动急性髓细胞白血病（AML）的发病机制，但它代表了成人AML患者预后不良的独立预测因素。因此，靶向menin-MLL融合蛋白相互作用的小分子抑制剂已经出现用于治疗MLL重排的AML。由于组蛋白去乙酰化酶（HDAC）和脑膜蛋白-MLL相互作用的抑制剂都靶向转录调控机制，涉及染色质重塑的表观遗传调控，控制肿瘤发生中相关基因的表达，我们假设这两类药物可能相互作用杀死MLL重排（MLL-r）AML细胞。在这里，我们报告了亚毒性剂量的HDAC抑制剂chidamide和menin-MLL相互作用抑制剂MI-3的联合治疗在体外和体内显示出对人MLL-r AML细胞的高度协同抗肿瘤活性，但不是那些没有这种遗传畸变的细胞。从机制上讲，共同暴露于西达米特和MI-3导致MLL-r AML细胞中的强烈凋亡，与线粒体膜电位的丧失和ROS产生的急剧增加有关。联合处理还破坏了CHK 1和CHK 2激酶水平的DNA损伤检查点，而不是其上游激酶（ATR和ATM），以及可能通过同源重组（HR）而不是非同源末端连接（NHEJ）的DNA修复。全基因组RNAseq揭示了涉及几种潜在信号传导途径的基因表达改变（例如，细胞周期、DNA修复、MAPK、NF-κB），其可能解释或有助于西达米特和MI-3作为单一药剂且特别是组合在MLL-r AML中的抗白血病活性的作用机制。总的来说，这些发现为进一步临床研究这种新的靶向策略提供了临床前基础，该策略结合HDAC和Menin-MLL相互作用抑制剂，以改善预后不良的MLL-r白血病患者亚组的治疗结果。
While the aberrant translocation of the mixed-lineage leukemia (MLL) gene drives pathogenesis of acute myeloid leukemia (AML), it represents an independent predictor for poor prognosis of adult AML patients. Thus, small molecule inhibitors targeting menin-MLL fusion protein interaction have been emerging for the treatment of MLL-rearranged AML. As both inhibitors of histone deacetylase (HDAC) and menin-MLL interaction target the transcription-regulatory machinery involving epigenetic regulation of chromatin remodeling that governs the expression of genes involved in tumorigenesis, we hypothesized that these two classes of agents might interact to kill MLL-rearranged (MLL-r) AML cells. Here, we report that the combination treatment with subtoxic doses of the HDAC inhibitor chidamide and the menin-MLL interaction inhibitor MI-3 displayed a highly synergistic anti-tumor activity against human MLL-r AML cells in vitro and in vivo, but not those without this genetic aberration. Mechanistically, co-exposure to chidamide and MI-3 led to robust apoptosis in MLL-r AML cells, in association with loss of mitochondrial membrane potential and a sharp increase in ROS generation. Combined treatment also disrupted DNA damage checkpoint at the level of CHK1 and CHK2 kinases, rather than their upstream kinases (ATR and ATM), as well as DNA repair likely via homologous recombination (HR), but not non-homologous end joining (NHEJ). Genome-wide RNAseq revealed gene expression alterations involving several potential signaling pathways (e.g., cell cycle, DNA repair, MAPK, NF-κB) that might account for or contribute to the mechanisms of action underlying anti-leukemia activity of chidamide and MI-3 as a single agent and particularly in combination in MLL-r AML. Collectively, these findings provide a preclinical basis for further clinical investigation of this novel targeted strategy combining HDAC and Menin-MLL interaction inhibitors to improve therapeutic outcomes in a subset of patients with poor-prognostic MLL-r leukemia.