Menin-Mixed Lineage Leukemia protein-protein interaction complex (Menin-MLL complex)

The Menin-Mixed Lineage Leukemia (Menin-MLL) protein-protein interaction complex is a critical epigenetic regulator involved in the pathogenesis of specific subsets of acute leukemia (PubMed: 28263184). Menin, a protein encoded by the MEN1 gene, acts as a scaffold that binds to the N-terminus of the MLL1 (KMT2A) protein or its oncogenic fusion derivatives (UniProt: O00255, Q03164). This interaction is essential for the localization of MLL-fusion proteins to specific genomic loci, where they drive the overexpression of leukemogenic genes such as HOXA9 and MEIS1, leading to a block in hematopoietic differentiation and uncontrolled cell proliferation (PubMed: 36921593). Therapeutic targeting of this complex involves small-molecule inhibitors, such as revumenib and ziftomenib, that occupy the menin binding pocket, effectively displacing MLL and reversing the leukemic gene expression profile (PubMed: 36921593, ClinicalTrials.gov: NCT04065399). This approach has shown significant clinical promise in patients with MLL-rearranged or NPM1-mutated leukemias, though challenges such as differentiation syndrome and the emergence of resistance mutations in the MEN1 gene have been observed in clinical trials (PubMed: 36921597).

Other names

Menin-KMT2A complexMenin-MLL1 complexMEN1-KMT2A interactionMenin-MLL fusion protein complex

Small molecule inhibition of the protein-protein interaction between the scaffold protein menin and the N-terminus of MLL1 (KMT2A) or MLL-fusion proteins, which disrupts the recruitment of the MLL complex to leukemogenic target genes like HOXA9 and MEIS1.