Effective therapy of AML with RUNX1 mutation by co-treatment with inhibitors of protein translation and BCL2 [ATAC-seq]

Majority of RUNX1 mutations in AML are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared to AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1 and c-Myc. Compared to AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. HHT treatment repressed enhancers and their BRD4 occupancy, as well as reduced levels of c-Myc, c-Myb, MCL1 and Bcl-xL. Consistent with this, co-treatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared to each agent alone, co-treatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1. 12 samples; replicates are included and controls are provided for each data set

急性髓系白血病（acute myeloid leukemia, AML）中绝大多数RUNX1突变为错义突变或缺失截短突变，且以功能丧失型突变为主要表现形式。接受标准治疗后，携带突变型RUNX1（mtRUNX1）的AML患者临床预后劣于未携带RUNX1突变的患者。本研究结果显示，与未携带mtRUNX1的AML细胞相比，同基因背景下携带mtRUNX1的AML细胞表现出核糖体生物发生受损、分化障碍，同时野生型RUNX1、PU.1及c-Myc的表达水平降低。相较于仅携带野生型RUNX1的AML细胞，携带mtRUNX1的AML细胞对蛋白质翻译抑制剂高三尖杉酯碱（homoharringtonine, omacetaxine）以及BCL2抑制剂维奈克拉（venetoclax）更为敏感。高三尖杉酯碱（HHT）处理可抑制增强子区域，并降低BRD4在增强子上的结合占有率，同时使c-Myc、c-Myb、MCL1及Bcl-xL的蛋白水平降低。与此一致的是，联合使用omacetaxine与venetoclax或BET抑制剂（BET inhibitor），可在携带mtRUNX1的AML细胞中产生协同体外杀伤效应。相较于单一药物治疗，联合使用omacetaxine与venetoclax或BET抑制剂还可提升体内抗AML疗效，同时延长携带mtRUNX1 AML细胞移植后的免疫耗竭小鼠的生存期。本研究结果凸显了基于omacetaxine的联合疗法在治疗携带mtRUNX1的AML中的优异疗效。本数据集包含12份样本，设置了生物学重复，并为每个数据集提供了对照。