Inhibition of menin in acute myeloid leukemia (AML) harboring histone-lysine-N-methyltransferase 2A rearrangement (KMT2Ar) or the mutated Nucleophosmin gene (NPM1c) is considered a novel and effective treatment approach in these patients. However, rapid acquisition of resistance mutations can impair treatment success. In patients with elevated retinoic acid receptor alpha (RARA) expression levels, promising effects are demonstrated by the next-generation RARalphaagonist tamibarotene, which restores differentiation or induces apoptosis. In this study, the combination of revumenib and tamibarotene was investigated in various KMT2Ar or NPM1c AML cell lines and patient-derived blasts, focusing on the potential synergistic induction of differentiation or apoptosis. Both effects were analyzed by flow cytometry and validated by Western blot analysis. Synergy calculations were performed using viability assays. Regulation of the relevant key mediators for the MLL complex were quantified by RT-qPCR. In MV4:11 cells characterized by the highest relative mRNA levels of RARA, highly synergistic induction of apoptosis is demonstrated upon combination treatment. Induction of apoptosis by combined treatment of MV4:11 cells is accompanied by pronounced induction of the pro-apoptotic protein BAX and a synergistic reduction in CDK6 mRNA levels. In MOLM13 and OCI-AML3 cells, an increase in differentiation markers like PU.1 or a decreased ratio of phosphorylated to total CEBPA is demonstrated. In parts, corresponding effects were observed in patient-derived AML cells carrying either KMT2Ar or NPM1c. The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics.
在携带组蛋白赖氨酸N-甲基转移酶2A重排（KMT2Ar）或突变型核磷蛋白基因（NPM1c）的急性髓系白血病（AML）中，抑制menin蛋白被认为是一种新颖且有效的治疗策略。然而，耐药突变的快速获得可能影响治疗效果。对于维甲酸受体α（RARA）表达水平升高的患者，新一代RARα激动剂他米巴罗汀显示出良好疗效，可恢复细胞分化或诱导细胞凋亡。本研究在多种KMT2Ar或NPM1c AML细胞系及患者来源的原始细胞中，探讨了revumenib与他米巴罗汀的联合治疗方案，重点关注其对细胞分化或凋亡的协同诱导作用。通过流式细胞术分析两种效应，并采用蛋白质印迹法进行验证。细胞活力实验用于协同效应计算，RT-qPCR技术定量分析MLL复合体关键调控因子的表达变化。在RARA相对mRNA水平最高的MV4:11细胞中，联合治疗显示出显著的协同凋亡诱导效应。该细胞凋亡过程伴随促凋亡蛋白BAX的显著上调及CDK6 mRNA水平的协同降低。在MOLM13和OCI-AML3细胞中，观察到PU.1等分化标志物的增加，以及磷酸化与总CEBPA比值的下降。在部分携带KMT2Ar或NPM1c的患者来源AML细胞中也观察到相应效应。revumenib与他米巴罗汀联用能显著增强对KMT2Ar或NPM1c AML细胞的干预效果，展现出协同分化诱导或凋亡启动作用。这些发现为具有特定分子特征的复发/难治性AML患者提供了有前景的治疗策略。
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