Menin – Lysine methyltransferase 2A interaction interface (Menin-KMT2A)

The Menin-KMT2A interaction interface is a critical epigenetic regulatory site involved in the pathogenesis of specific acute leukemias. Menin, a protein encoded by the MEN1 gene, acts as a scaffold that binds to the N-terminus of Lysine Methyltransferase 2A (KMT2A), also known as MLL1 (UniProt O00255, Q03164). This interaction is essential for the stability and chromatin localization of the KMT2A complex, which regulates the expression of homeobox (HOX) genes. In leukemias with KMT2A rearrangements or NPM1 mutations, the Menin-KMT2A complex drives the constitutive overexpression of HOXA9 and MEIS1, leading to a block in myeloid differentiation (Issa et al., Nature 2023). Small-molecule inhibitors targeting this interface disrupt the binding of Menin to KMT2A, effectively turning off the leukemogenic transcriptional program. This disruption induces the differentiation of leukemic blasts into functional myeloid cells and triggers cell cycle arrest. Clinical candidates such as revumenib and ziftomenib have shown significant therapeutic potential in treating relapsed or refractory acute myeloid leukemia and acute lymphoblastic leukemia. However, the emergence of resistance mutations within the Menin binding pocket presents a challenge for long-term efficacy. Overall, targeting this interface represents a precision medicine approach for genetically defined subsets of leukemia patients.

Other names

Menin-MLL1 interactionMenin-MLL interfaceMEN1-KMT2A complexMenin-KMT2A PPI

Small-molecule inhibition of the protein-protein interaction between Menin and the N-terminus of KMT2A (MLL1), which prevents the recruitment of the KMT2A complex to leukemogenic target genes and disrupts the oncogenic transcriptional program.