Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.
Menin抑制剂（MI）治疗可破坏Menin与MLL1或MLL1融合蛋白（FP）之间的相互作用，抑制HOXA9/MEIS1表达，诱导携带MLL1重排（r）及FP或表达突变型（mt）NPM1的急性髓系白血病细胞分化并丧失存活能力。尽管MI治疗后常出现临床应答，但多数携带MLL1-r或mt-NPM1的AML患者最终仍死于疾病。本文展示的临床前研究表明，Menin的基因敲除或降解，或采用MI药物SNDX-50469治疗，能降低MLL1/MLL1-FP靶基因表达，这与MI诱导的分化及活力丧失相关。MI治疗还会减弱BCL2和CDK6水平。SNDX-50469与BCL2抑制剂（维奈托克）或CDK6抑制剂（阿贝西利）联合处理，能在携带MLL1-r或mtNPM1的细胞系及患者来源AML细胞中产生协同致死效应。SNDX-5613与维奈托克的联合疗法在携带MLL1-r或mt-NPM1的细胞系或患者来源AML细胞异种移植模型中展现出更优的体内疗效。对于同时表达FLT3突变并经CRISPR编辑引入mtTP53的MLL1-r AML细胞，基于MI的联合方案仍能保持协同作用。这些发现为临床测试针对携带MLL1-r或mtNPM1的AML的MI联合疗法提供了前景。
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