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Simple Summary: This study investigates the combined therapeutic potential of revumenib and tamibarotene in acute myeloid leukemia (AML) with histone-lysine-N-methyltransferase 2A rearrangement (KMT2Ar) or mutated Nucleophosmin gene (NPM1c). Menin inhibition is considered a promising treatment for such AML cases, but resistance mutations pose challenges. Elevated retinoic acid receptor alpha (RARA) expression levels indicate favorable outcomes with tamibarotene, known for restoring differentiation or inducing apoptosis. The combination of revumenib and tamibarotene demonstrated highly synergistic effects in MV4:11 cells, marked by apoptosis induction while MOLM13 and OCI-AML3 cells showed increased differentiation markers. Patient-derived AML cells exhibited in parts corresponding effects, suggesting a potential strategy for relapsed/refractory AML patients with specific molecular characteristics. 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 RARalpha agonist 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. [ABSTRACT FROM AUTHOR]