Menin-Mixed Lineage Leukemia 1 protein complex (Menin-MLL1 complex)

The menin-MLL1 protein-protein interaction represents a critical oncogenic complex in acute leukemias bearing MLL gene translocations. Menin functions as a scaffold protein that recruits the histone methyltransferase MLL1 and MLL fusion proteins to promoters of target genes, particularly Hox genes such as Hoxa9 and Meis1, through a bivalent binding mechanism involving two menin-binding motifs. This interaction drives sustained expression of these oncogenes, which is essential for MLL fusion protein-driven leukemogenesis. The crystal structures of menin bound to MLL peptides and small-molecule inhibitors have revealed a large central cavity in menin that accommodates the MLL peptide, enabling structure-based drug design. Potent small-molecule menin-MLL inhibitors, such as MI-1481 (IC50 = 3.6 nM), have been developed and demonstrate selective activity in MLL leukemia cells, causing proliferation inhibition, downregulation of Hoxa9, and cell differentiation. These inhibitors represent a promising therapeutic strategy for aggressive leukemias with MLL rearrangements by directly blocking the oncogenic menin-MLL interaction at the molecular level.

Other names

Menin-MLL interactionMLL1-Menin complexMixed Lineage Leukemia 1-Menin interactionMLL fusion protein-Menin interaction (when referring to MLL fusion variants)

Small molecules bind to the MLL-binding pocket in menin and competitively block MLL peptide binding. Inhibitors effectively displace the bivalent MLL fragment (encompassing MBM1 and MBM2 motifs) from menin. Blocking the interaction prevents recruitment of MLL1 and MLL fusion proteins to target gene promoters. Downstream effects include reduced Hoxa9 expression and cell differentiation in MLL leukemia cells. Inhibitors achieve potency through multiple interaction modes with key menin residues (Tyr276, Trp341, Glu366).