Menin-Histone-lysine N-methyltransferase 2A (Menin-MLL) complex (Menin-MLL complex)

The Menin-MLL/KMT2A protein-protein complex is a critical epigenetic regulator involved in the maintenance of gene expression patterns during hematopoiesis (UniProt: O00255, Q03164). Menin, encoded by the MEN1 gene, acts as a scaffold protein that binds to the N-terminal fragment of Histone-lysine N-methyltransferase 2A (KMT2A, also known as MLL1) (PubMed: 15964822). In certain leukemias, chromosomal rearrangements of the KMT2A gene produce MLL-fusion proteins that rely on the interaction with Menin to localize to specific genomic loci, such as the HOXA and MEIS1 clusters (PubMed: 22237106). This interaction drives the aberrant expression of pro-leukemogenic genes, preventing myeloid differentiation and promoting leukemic cell survival. Therapeutic targeting of this complex involves small molecules that occupy the Menin binding pocket, effectively disrupting the interaction with MLL or MLL-fusion proteins (PubMed: 36071110). This disruption leads to the downregulation of leukemogenic programs and induces terminal differentiation of the malignant cells. Clinical development of Menin inhibitors, such as Revumenib and Ziftomenib, has shown significant promise in treating MLL-rearranged and NPM1-mutated acute leukemias (NCT04065399, NCT04067336).

Other names

MEN1-KMT2A complexMenin-MLL1 complexMenin-KMT2A interactionMenin-MLL fusion protein complex

Small molecule inhibition of the protein-protein interaction between Menin and the N-terminus of MLL1/KMT2A, leading to the displacement of the MLL fusion complex from chromatin and subsequent differentiation of leukemic cells (PubMed: 36071110).