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In some leukaemias a broken chromatin protein (KMT2A, once called MLL) or a mutant NPM1 keeps embryonic growth genes (HOXA9, MEIS1) switched on, so blood cells never mature. Both need a partner called menin to stay on the DNA. Menin inhibitors pull the plug and the cells mature; the first was approved in 2024.
KMT2A (MLL1) is a histone H3K4 methyltransferase that, fused to one of more than 80 partner genes by chromosomal translocation, becomes a leukaemia driver in infant ALL and in about 10% of adult AML (often therapy-related). The fusion protein is tethered to chromatin through menin (MEN1) and LEDGF, and recruits DOT1L (H3K79 methylation) to keep HOXA9 and MEIS1 transcribed; these homeobox genes hold the cell in a stem-like, undifferentiated state. Mutant NPM1 (about 30% of adult AML), mislocalised to the cytoplasm, drives the same HOX programme and is equally menin-dependent. Small molecules that occupy the KMT2A-binding pocket of menin (revumenib, ziftomenib, bleximenib, enzomenib) release the complex from chromatin, HOXA9 and MEIS1 fall, and the blasts differentiate. Revumenib was approved in 2024 for relapsed or refractory KMT2A-rearranged acute leukaemia (AUGMENT-101) and ziftomenib in 2025 for NPM1-mutant AML (KOMET-001). Differentiation syndrome and QT prolongation are the class toxicities; acquired MEN1 mutations at the drug-binding site are the resistance mechanism.
Two hands are needed to hold a switch down: KMT2A (or mutant NPM1) is one hand and menin is the other. As long as both hold, the 'stay immature' genes stay on. Menin inhibitors slip a wedge under menin's hand, the switch springs up and the leukaemia cells finish growing up into normal blood cells.
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