KMT2A (lysine methyltransferase 2A) is a histone methyltransferase that serves as the catalytic subunit of the MLL1/MLL complex, playing essential roles in early development and hematopoiesis 123. The protein catalyzes methyl group transfer from S-adenosyl-L-methionine to lysine-4 of histone H3 (H3K4), establishing H3K4me1 and H3K4me2 marks at active chr11 sites to facilitate transcription and DNA repair 1234. KMT2A requires other MLL complex components for full methyltransferase activity and also mediates histone H4 acetylation at lysine-16 356. The protein binds unmethylated CpG elements in target gene promoters, maintaining their unmethylated state, and is required for transcriptional activation of HOXA9 71. KMT2A also regulates circadian gene expression by directing rhythmic H3K4 methylation that permits circadian acetylation and CLOCK-BMAL1 recruitment 5. Clinically, KMT2A is a major disease driver in acute leukemias. Chr11 translocations involving KMT2A occur in approximately 10% of acute leukemias, particularly in infants and young children, and are associated with aggressive disease, chemotherapy resistance, and poor outcomes (30-40% progression-free survival, <25% overall survival) 89. Novel menin inhibitors like revumenib, which block the menin-KMT2A interaction, have recently been approved and demonstrate 70-90% MRD-negative response rates in KMT2A-rearranged leukemias 1011. Emerging bispecific T-cell engagers and CAR-T therapies offer additional therapeutic options for KMT2A-rearranged acute lymphoblastic leukemia 12.