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

Menin is a scaffold protein encoded by the MEN1 gene that serves as a critical oncogenic cofactor for the Lysine methyltransferase 2A (KMT2A) protein, also known as Mixed Lineage Leukemia 1 (MLL1) [1, 4]. In leukemias characterized by KMT2A rearrangements, the resulting fusion proteins must bind to Menin to localize to specific chromatin sites and drive the expression of leukemogenic genes, such as HOXA9 and MEIS1 [5, 13]. This interaction is also essential for the survival of leukemic cells harboring NPM1 mutations or NUP98 rearrangements [1, 16]. Therapeutic strategies focus on small-molecule inhibitors that occupy the KMT2A-binding pocket on Menin, thereby disrupting the protein-protein interaction [3, 11]. This disruption leads to the silencing of oncogenic transcriptional programs, promoting the differentiation of leukemic blasts into mature blood cells and inducing apoptosis [13, 17]. Clinical trials of Menin inhibitors, including the recently approved revumenib, have demonstrated significant clinical activity in patients with relapsed or refractory acute leukemias [6, 9].

Other names

Menin–Mixed Lineage Leukemia interactionMenin–MLL interactionMEN1–KMT2A interactionMenin–MLL1 interactionMenin–KMT2A complex

Inhibition of the protein-protein interaction between Menin and the N-terminus of Lysine methyltransferase 2A (KMT2A/MLL1), preventing the recruitment of oncogenic fusion complexes to target gene promoters and disrupting pro-leukemic transcriptional programs [1, 13, 16].