Variable Response of MLL-Rearranged Leukemia Cell Lines to Combinations of Menin, CDK9 and DOT1L Inhibitors

Background: MLL (Mixed Lineage Leukemia) rearrangements occur in approximately 10% of leukemias. Infant leukemia has a higher frequency of MLL rearrangement (MLL-r) than leukemia in other age groups. Despite intensified treatment in infant leukemia, outcomes remain poor. MLL-r leukemia depends on the interaction of MLL fusions with menin, DOT1L, and CDK9. Single-agent treatment with menin, DOT1L, and CDK9 inhibitors has shown promising results in preclinical studies, but their clinical efficacy has been limited by primary and acquired resistance. We hypothesized that combination therapy targeting multiple regulators, including menin, DOT1L, and CDK9, would provide a more effective treatment of MLL-r leukemia.