Menin-Lysine Methyltransferase 2A protein-protein interaction interface (Menin-KMT2A interface)

Menin is a scaffold protein encoded by the MEN1 gene that serves as a critical adapter for the Lysine Methyltransferase 2A (KMT2A/MLL1) complex, facilitating its recruitment to specific gene promoters. In leukemias characterized by KMT2A rearrangements or NPM1 mutations, the interaction between Menin and the KMT2A protein is essential for maintaining the expression of homeobox (HOX) genes and MEIS1, which collectively block hematopoietic differentiation and drive leukemogenesis (Krivtsov & Armstrong, 2007, Nature Reviews Cancer). By binding to a deep pocket on the surface of Menin, small-molecule inhibitors competitively block the KMT2A binding site, effectively dismantling the oncogenic transcriptional machinery (Huang et al., 2023, Signal Transduction and Targeted Therapy). This therapeutic strategy has shown clinical promise in inducing complete remissions in patients with genetically defined subsets of acute leukemia (Issa et al., 2023, Nature). Beyond its role in leukemia, the Menin-KMT2A interface is a focal point for understanding epigenetic regulation and chromatin biology in both normal and malignant states (UniProt O00255).

Other names

Menin-MLL1 interactionMEN1-KMT2A complexMenin-Mixed Lineage Leukemia 1 interfaceMenin-MLL interface

Small-molecule inhibition of the protein-protein interaction between Menin and the N-terminus of KMT2A (MLL1), which displaces the MLL-fusion protein or wild-type MLL complex from chromatin, leading to the downregulation of leukemogenic genes like HOXA9 and MEIS1 and inducing myeloid differentiation.