Menin–Mixed-lineage leukemia 1 protein–protein interaction interface (Menin–MLL1) (Menin–MLL1 interface)

The Menin–MLL1 protein–protein interaction interface is a critical therapeutic target in specific subtypes of acute leukemia, particularly those involving MLL1 (KMT2A) rearrangements or NPM1 mutations (Krivtsov et al., Cancer Cell 2012). Menin, a scaffold protein encoded by the MEN1 gene, binds to the N-terminal fragment of MLL1 or MLL-fusion proteins, facilitating their recruitment to target genes such as HOXA9 and MEIS1 (UniProt O00255). This interaction is essential for maintaining the expression of pro-leukemogenic genes that block hematopoietic differentiation and promote self-renewal (Issa et al., Nature 2023). Small molecule inhibitors designed to occupy the Menin binding pocket disrupt this complex, leading to the downregulation of these oncogenic drivers and inducing terminal differentiation of leukemic blasts. Clinical development of Menin–MLL1 inhibitors, such as revumenib and ziftomenib, has shown significant promise in treating refractory or relapsed acute myeloid leukemia and acute lymphoblastic leukemia. However, challenges such as the development of resistance mutations in the MEN1 binding site and clinical toxicities like differentiation syndrome remain areas of active investigation (Perner et al., Nature 2023).

Other names

Menin–KMT2A interactionMenin–MLL complexMEN1–KMT2A interfaceMenin–MLL1 PPI

Small molecule inhibitors bind to the Menin protein at the specific pocket where MLL1 (KMT2A) normally attaches, sterically hindering the formation of the Menin-MLL complex (Krivtsov et al., Cancer Cell 2012). This displacement prevents the recruitment of MLL-fusion proteins or wild-type MLL1 to target gene promoters such as HOXA9 and MEIS1, thereby inhibiting the leukemogenic transcriptional program and inducing terminal differentiation and apoptosis in malignant cells (Issa et al., Nature 2023).