Menin-Mixed lineage leukemia 1 protein-protein interaction (Menin-MLL1 PPI)

The Menin-MLL1 protein-protein interaction is a critical epigenetic regulatory mechanism involving the scaffold protein Menin (encoded by MEN1) and the histone methyltransferase Mixed Lineage Leukemia 1 (MLL1, also known as KMT2A) (UniProt: O00255, Q03164). In certain leukemias, particularly those involving MLL1 rearrangements (KMT2Ar) or NPM1 mutations, Menin acts as an essential cofactor that tethers MLL fusion proteins or wild-type MLL1 to specific genomic loci, such as the HOXA and MEIS1 gene clusters (PubMed: 26000484). This recruitment drives the constitutive expression of pro-leukemogenic genes, which blocks hematopoietic differentiation and promotes uncontrolled cell proliferation (PubMed: 15964277). Therapeutic strategies focus on small molecule inhibitors that occupy the MLL-binding pocket on Menin, effectively disrupting the complex and reversing the leukemogenic gene expression profile (PubMed: 36922593). Clinical trials, such as those for revumenib and ziftomenib, have demonstrated that inhibiting this interaction can induce profound clinical responses and promote the differentiation of blast cells into mature myeloid cells (Nature: Issa et al., 2023). However, challenges such as the development of resistance mutations in the MEN1 gene and clinical toxicities like differentiation syndrome and QTc prolongation remain areas of active investigation (PubMed: 36922593).

Other names

Menin-KMT2A interactionMEN1-KMT2A complexMenin-MLL interactionMenin-MLL1 complex

Small molecule inhibition of the Menin-MLL1 protein-protein interaction by binding to the Menin pocket, preventing the recruitment of MLL fusion proteins or wild-type MLL1 to target gene promoters like HOXA and MEIS1, thereby inducing cell cycle arrest and myeloid differentiation (PubMed: 36922593).