Menin-mixed lineage leukemia (Menin-MLL) protein-protein interface (Menin-MLL)

The menin-mixed lineage leukemia (MLL) protein-protein interface is a critical epigenetic regulatory site and a high-priority therapeutic target in hematologic malignancies (Issa et al., 2023). Menin, a scaffold protein encoded by the MEN1 gene, binds to the N-terminus of MLL1 (also known as KMT2A) to facilitate the recruitment of the MLL complex to specific gene promoters (UniProt, 2024). These promoters include HOXA and MEIS1, which are essential for maintaining a leukemic state and preventing cell differentiation (Kura Oncology, 2024). In leukemias characterized by MLL rearrangements (MLL-r) or NPM1 mutations, this interaction is hijacked to drive the constitutive expression of pro-proliferative genes (Syndax Pharmaceuticals, 2024). Small molecule inhibitors targeting this interface occupy the menin binding pocket, effectively displacing MLL fusion proteins and leading to the downregulation of oncogenic drivers (Huang et al., 2023). Clinical development of menin-MLL inhibitors, such as revumenib and ziftomenib, has shown significant efficacy in relapsed/refractory acute leukemias (Stein et al., 2023). However, therapeutic challenges include the management of differentiation syndrome and the emergence of acquired resistance mutations in the MEN1 gene (Perner et al., 2023). This target represents a paradigm shift in treating genetically defined subsets of acute myeloid and lymphoblastic leukemias.

Other names

Menin-KMT2A interfaceMEN1-MLL1 complexMenin-MLL1 interactionMenin-MLL protein-protein interaction

Small molecule inhibitors bind to the menin protein at the specific pocket where it interacts with the N-terminus of MLL (KMT2A), preventing the formation of the menin-MLL complex. This disruption leads to the downregulation of leukemogenic target genes, such as HOXA9 and MEIS1, thereby reversing the differentiation block in leukemic cells and promoting apoptosis.