文章：

同时靶向GFI1/KDM1A与BRD4对AML及MPN后继发性AML细胞具有更优疗效

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

原文发布日期：2021-05-20

DOI: 10.1038/s41408-021-00487-3

类型: Article

开放获取: 是

英文摘要：

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.
 

摘要翻译： 

目前亟需克服非遗传性治疗抵抗以改善急性髓系白血病（AML）的预后，特别是在髓系增殖性肿瘤（MPN）后继发性AML中。相关研究揭示了通过基因敲除、降解或小分子靶向抑制GFI1/LSD1对活性增强子的影响，从而改变基因表达、诱导AML及MPN继发性AML细胞分化和死亡。在经LSD1（KDM1A）抑制剂处理的AML细胞中进行的聚焦蛋白结构域的CRISPR筛选发现，BRD4、MOZ、HDAC3和DOT1L属于协同依赖性因子。我们的研究证实，在AML和MPN后继发性AML细胞中，联合靶向LSD1与任一协同依赖性因子可在体外产生协同致死效应。LSD1抑制剂与JAK抑制剂鲁索替尼联合处理对MPN后继发性AML细胞同样具有协同致死作用。LSD1抑制剂预处理可诱导GFI1、PU.1和CEBPα表达，同时消耗c-Myc，从而克服MPN后继发性AML细胞对鲁索替尼或BET抑制剂的非遗传性抵抗。LSD1抑制剂与BET抑制剂或鲁索替尼的联合治疗在体内对MPN后继发性AML细胞表现出更优疗效。这些发现凸显了基于LSD1抑制剂的联合治疗方案值得进行临床疗效验证，尤其对于克服AML及MPN后继发性AML的非遗传性治疗抵抗具有重要意义。

原文链接：

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells