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

The menin–KMT2A protein–protein interaction interface is a critical therapeutic target in specific subsets of acute leukemia, particularly those involving KMT2A (MLL1) rearrangements or NPM1 mutations (Issa et al., 2023, Nature). Menin, a protein encoded by the MEN1 gene, acts as an essential scaffold for KMT2A, a histone methyltransferase that regulates the expression of homeobox (HOX) genes (Kohlmann et al., 2023, Nature). In leukemias driven by MLL-fusion proteins, the interaction with menin is required to tether the oncogenic complex to chromatin, maintaining the expression of pro-leukemogenic genes like HOXA9 and MEIS1 (Kura Oncology, 2024). Small molecule inhibitors designed to bind the menin pocket and block KMT2A binding lead to the downregulation of these genes, triggering differentiation and apoptosis of leukemic blasts (Syndax Pharmaceuticals, 2024). This target represents a precision medicine approach, with several inhibitors currently in clinical trials showing significant efficacy in genetically defined patient populations (PubMed, PMID: 36823310). Notable safety concerns include differentiation syndrome and the potential for acquired resistance through mutations in the MEN1 gene (Perner et al., 2023, Nature).

Other names

Menin–MLL1 interfaceMenin–MLL interactionMEN1–KMT2A complexMenin–Mixed Lineage Leukemia 1 interaction

Small molecule inhibition of the menin–KMT2A interaction, which disrupts the recruitment of MLL-fusion proteins or wild-type MLL complexes to target genes like HOXA9 and MEIS1, inducing cell cycle arrest and differentiation (Issa et al., 2023, Nature).