Menin inhibitors block the essential menin-MLL1 interaction, which disrupts the chromatin complex, inhibits HOXA9/MEIS1-mediated leukemogenesis, and induces differentiation. This pathway is critical in KMT2Ar AML. NPM1-mutated and NUP98- rearranged leukemias are also dependent on menin binding and aberrant HOXA9/MEIS1 expression and sensitive to this therapeutic strategy as well.