TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous cancer that is associated with poor outcomes. Revumenib and other menin inhibitors have shown promising activity against AMLs with KMT2A -rearrangements or NPM1 mutations. However, mechanisms of de novo resistance have not yet been elucidated. We analyzed a panel of cell lines and generated an isogenic model to assess the impact of TP53 mutations on the response of AML cells to revumenib. TP53 mutations are associated with de novo resistance to revumenib, impaired induction of TP53 transcriptional targets, and deregulated expression of the BH3 proteins BCL-2 and MCL-1. The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized TP53 -mutant AML cells to revumenib. These data identify mutant TP53 as a potential biomarker for de novo resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients KMT2A -rearranged leukemias with TP53 mutations.