Menin–Lysine Methyltransferase 2A protein–protein interaction (Menin–KMT2A PPI)

Menin is a scaffold protein encoded by the MEN1 gene that plays a critical role in regulating gene expression by interacting with the N-terminus of Lysine Methyltransferase 2A (KMT2A, also known as MLL1) [UniProt O00255]. This interaction occurs at a specific site known as the menin MLL-binding groove, which is essential for the stability and chromatin localization of the MLL complex [Yokoyama et al., 2005]. In leukemias involving KMT2A rearrangements (KMT2Ar) or NPM1 mutations, this protein-protein interaction is hijacked to drive the expression of leukemogenic genes like HOXA9 and MEIS1 [Krivtsov & Armstrong, 2007]. By tethering MLL-fusion proteins to these target genes, the interaction prevents hematopoietic differentiation and promotes the survival of leukemic blasts [Kuhn et al., 2016]. Therapeutic strategies focus on small-molecule inhibitors that bind to the menin MLL-binding groove, effectively displacing KMT2A or its fusion partners from menin [Grembecka et al., 2012]. This disruption leads to the downregulation of the oncogenic transcriptional program, inducing cell cycle arrest and terminal differentiation of the cancer cells [Issa et al., 2023]. Clinical trials for inhibitors such as revumenib and ziftomenib have shown promising results in patients with relapsed or refractory acute leukemias [Stein et al., 2023]. Consequently, the menin–KMT2A interaction represents a high-value target for precision medicine in hematologic malignancies.

Other names

Menin–MLL1 interactionMenin–MLL interactionMenin–KMT2A complexMEN1–KMT2A interactionMenin–MLL binding groove

Competitive inhibition of the Menin–KMT2A protein–protein interaction at the MLL-binding groove, leading to displacement of the MLL-fusion protein complex from chromatin and subsequent downregulation of leukemogenic genes.