文章：

靶向表观遗传共依赖性增强Menin抑制剂在MLL1重排或NPM1突变AML中的抗白血病疗效

Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1

原文发布日期：2023-04-13

DOI: 10.1038/s41408-023-00826-6

类型: Article

开放获取: 是

英文摘要：

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse.
 

摘要翻译： 

采用Menin抑制剂（例如SNDX-5613）单药治疗，可在携带MLL1重排或NPM1突变的复发/难治性急性髓系白血病患者中诱导临床缓解，但多数患者要么未能产生应答，要么最终复发。通过运用单细胞RNA测序、染色质免疫沉淀测序、ATAC测序、RNA测序、反相蛋白微阵列及质谱流式细胞术等多维分析，现有临床前研究阐明了Menin抑制剂对携带MLL1重排或NPM1突变的AML细胞产生疗效相关的基因表达特征。值得注意的是，在MLL融合蛋白靶基因位点处，研究者观察到Menin抑制剂介导的全基因组范围内ATAC-seq与RNA-seq峰值的对数倍变化扰动具有一致性，同时伴随与AML分化相关的mRNA表达上调。Menin抑制剂治疗还减少了表达干细胞/祖细胞标志的AML细胞数量。在MLL1重排AML细胞中进行的聚焦蛋白结构域的CRISPR-Cas9筛选，鉴定出可与Menin抑制剂协同治疗的特异性共依赖靶点，包括BRD4、EP300、MOZ和KDM1A。与此一致的是，在体外实验中，Menin抑制剂与BET抑制剂、MOZ抑制剂、LSD1抑制剂或CBP/p300抑制剂的联合使用，对携带MLL1重排或NPM1突变的AML细胞产生了协同致死效应。在MLL1重排AML的异种移植模型中，Menin抑制剂与BET抑制剂或CBP/p300抑制剂的联合治疗也展现出显著更优的体内疗效。这些发现揭示了基于Menin抑制剂的新型联合疗法，有望预防Menin抑制剂单药治疗后AML干细胞/祖细胞的逃逸，而这正是治疗难治性AML复发的关键因素。

原文链接：

Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1