Menin – KMT2A interaction site on menin (Menin-KMT2A site)

The Menin – KMT2A interaction site on the protein menin is a critical therapeutic target in the treatment of specific subsets of acute leukemia. Menin, encoded by the MEN1 gene, acts as a nuclear scaffold protein and a key cofactor for the histone methyltransferase KMT2A (also known as MLL1). In leukemias characterized by KMT2A rearrangements or NPM1 mutations, the physical interaction between menin and the N-terminus of KMT2A is essential for the stability of oncogenic transcriptional complexes on chromatin. These complexes drive the overexpression of leukemogenic genes, such as HOXA9 and MEIS1, which block hematopoietic differentiation and promote malignant cell proliferation. Small molecule inhibitors, such as revumenib and ziftomenib, are designed to bind with high affinity to the KMT2A-binding pocket on menin, effectively disrupting this protein-protein interaction. This disruption leads to the displacement of the KMT2A complex from its target gene promoters, resulting in the downregulation of the leukemic program and the induction of myeloid differentiation and apoptosis. While this approach has shown significant clinical efficacy, particularly in relapsed or refractory cases, it is associated with specific safety concerns like differentiation syndrome and QTc prolongation. Furthermore, the emergence of acquired mutations within the menin binding pocket represents a significant challenge for long-term therapeutic durability.

Other names

Menin-MLL1 interaction siteMenin-KMT2A interfaceMenin-MLL interfaceMenin pocketKMT2A-binding pocket on menin

Small molecule inhibitors bind to the KMT2A-binding pocket on the surface of the menin protein, physically disrupting the interaction between menin and the N-terminus of KMT2A (also known as MLL1). This disruption displaces the oncogenic KMT2A-fusion complex from chromatin, leading to the rapid downregulation of leukemogenic driver genes such as HOXA9 and MEIS1, which subsequently relieves the differentiation block and induces apoptosis in leukemic blasts.