Menin–Lysine methyltransferase 2A (KMT2A) protein–protein interface (Menin–MLL interface)

The menin–Lysine methyltransferase 2A (KMT2A) protein–protein interface is a critical regulatory node in the epigenetic control of gene expression, particularly within the hematopoietic system [PubMed: 32814534]. Menin, a scaffold protein encoded by the MEN1 gene, binds to the amino-terminus of the KMT2A protein (formerly known as MLL1) [UniProt O00255, UniProt Q03164]. In leukemias characterized by KMT2A rearrangements or NPM1 mutations, this interaction is essential for the recruitment of oncogenic MLL-fusion proteins to genomic targets like the HOXA cluster and MEIS1, driving a pro-proliferative and anti-differentiation program [PubMed: 26000447, PubMed: 36543162]. Therapeutic targeting of this interface involves small-molecule inhibitors that occupy the menin binding pocket, effectively displacing the MLL-fusion complex from chromatin [PubMed: 31548605]. This disruption leads to the rapid downregulation of leukemogenic genes, inducing cell cycle arrest and terminal differentiation of malignant blasts [PubMed: 37644153]. Clinical development of menin inhibitors, such as revumenib and ziftomenib, has demonstrated significant efficacy in treating patients with these specific genetic alterations [PubMed: 36922555].

Other names

Menin–KMT2A complexMenin–MLL1 interactionMEN1–KMT2A interfaceMenin–MLL complex

Small-molecule inhibition of the protein-protein interaction between menin and the N-terminus of Lysine methyltransferase 2A (KMT2A), leading to the displacement of MLL-fusion proteins from chromatin and the subsequent transcriptional repression of oncogenic drivers such as HOXA9 and MEIS1 [PubMed: 31548605, PubMed: 36543162].