Histone-lysine N-methyltransferase 2A–menin complex (KMT2A–menin)

The histone-lysine N-methyltransferase 2A–menin complex comprises the enzyme KMT2A (also known as MLL1/MLL) and the scaffold protein menin. KMT2A is a histone methyltransferase that trimethylates lysine 4 of histone H3 (H3K4), a modification associated with active gene transcription. Menin, a product of the MEN1 gene, acts as a critical cofactor that binds the N-terminal region of KMT2A, recruiting it and its associated complex to chromatin at select gene promoters, most notably HOX gene loci. This interaction is essential for normal hemato- and neurodevelopment but is also co-opted in various leukemias—especially those with KMT2A rearrangements (KMT2Ar)—to maintain a leukemogenic transcriptional program centered on aberrant activation of HOX/MEIS1. Disruption of the menin–KMT2A complex with small-molecule inhibitors effectively blocks these transcriptional programs, providing a clinically validated therapeutic strategy in AML and ALL. This target is highly specific to a subset of developmental and leukemic gene expression pathways, making it a promising tool in epigenetic cancer therapy, though resistance and safety remain clinical challenges.

Other names

KMT2A–meninMLL1–meninmenin–KMT2AMLL1–MEN1 complexMLL–menin complex

Small-molecule inhibition of the menin–KMT2A interaction, blocking formation of the KMT2A–menin epigenetic complex, reducing aberrant HOX/MEIS1 gene transcription that drives leukemogenesis; Disruption of chromatin recruitment and methylation functions; Downregulation of leukemogenic transcriptional programs