Menin–Lysine methyltransferase 2A protein-protein interface (MEN1–KMT2A interface)

The Menin–KMT2A protein-protein interface is a pivotal epigenetic regulatory site and a high-priority therapeutic target in acute leukemias (Issa et al., 2023, Nature). Menin, a scaffold protein encoded by the MEN1 gene, binds to the N-terminus of the Lysine methyltransferase 2A (KMT2A, also known as MLL1) protein (Yokoyama et al., 2005, Cell). This interaction is essential for the localization of KMT2A complexes to target genes like HOXA9 and MEIS1, which are critical for maintaining hematopoietic stem cell programs (Krivtsov et al., 2006, Nature). In leukemias harboring KMT2A rearrangements or NPM1 mutations, the Menin–KMT2A complex is constitutively active, driving an oncogenic gene expression profile that prevents cellular differentiation. Therapeutic intervention involves small molecule inhibitors that competitively bind to the Menin pocket, disrupting its association with KMT2A and leading to the downregulation of leukemogenic targets (Stein et al., 2023, JAMA Oncology). Clinical candidates like revumenib and ziftomenib have demonstrated the ability to induce complete remissions by promoting the differentiation of leukemic blasts into mature myeloid cells. However, clinical management must address risks such as differentiation syndrome and the potential for acquired resistance through mutations in the MEN1 gene (Perner et al., 2023, Nature).

Other names

Menin–MLL1 interfaceMenin–Mixed lineage leukemia 1 interfaceMEN1–KMT2A complexMenin–KMT2A interaction

Small molecule inhibition of the protein-protein interaction between Menin and the N-terminus of KMT2A (MLL1), leading to the displacement of the KMT2A complex from chromatin and subsequent transcriptional silencing of leukemogenic genes.