Menin–lysine methyltransferase 2A protein complex (Menin–KMT2A (MLL1))

The menin–KMT2A complex is a critical chromatin-modifying protein complex formed by the nuclear scaffold protein menin (product of the MEN1 gene) and lysine methyltransferase 2A (KMT2A, also known as MLL1 or ALL-1). Menin acts as an adaptor, linking KMT2A to additional chromatin-modifying cofactors, including transcriptional co-activators such as LEDGF. KMT2A possesses histone methyltransferase activity, specifically mono-, di-, and trimethylating lysine 4 of histone H3 (H3K4), a mark associated with gene activation. In healthy hematopoiesis, the menin–KMT2A complex is essential for normal gene regulation, particularly of the HOX family genes. In leukemia, especially those with KMT2A rearrangements, the interaction of menin with KMT2A fusion proteins drives abnormal gene expression programs (especially HOX/MEIS1 upregulation), promoting malignant proliferation and impaired differentiation. Disrupting this interaction via small molecule inhibitors impairs leukemic cell growth, providing a promising therapeutic approach for KMT2A-rearranged and NPM1-mutant leukemias. The clinical use of menin–KMT2A inhibitors is being explored for these indications, but safety concerns remain around on-target hematopoietic toxicity and acquired resistance.

Other names

Menin–MLL1Menin–KMT2A complexMenin–mixed-lineage leukemia 1 complexMEN1–KMT2AMenin–ALL-1 complexMenin–HRX complex

Inhibition of menin–KMT2A interaction blocks assembly of oncogenic transcriptional complexes, reducing aberrant HOX/MEIS1 gene expression driving leukemogenesis. Allosteric or competitive inhibition at protein–protein interaction interface. Disruption of chromatin complex formation required for leukemic cell survival and proliferation.