Menin-Lysine methyltransferase 2A protein-protein interaction (Menin-KMT2A PPI)

The Menin-KMT2A (formerly MLL1) protein-protein interaction is a critical epigenetic regulatory mechanism frequently co-opted in hematologic malignancies. Menin, encoded by the MEN1 gene, acts as a scaffold protein that binds to the N-terminus of KMT2A, facilitating the recruitment of the KMT2A complex to specific gene promoters. In leukemias characterized by KMT2A rearrangements (KMT2Ar) or NPM1 mutations, this interaction is essential for the constitutive expression of homeobox genes (e.g., HOXA9) and MEIS1, which drive leukemogenesis and block hematopoietic differentiation. Small molecule inhibitors targeting this interaction bind to the Menin pocket where KMT2A normally docks, effectively disrupting the transcriptional complex. This disruption leads to the loss of the leukemogenic gene expression profile and promotes the terminal differentiation of blast cells. Clinical development of Menin-KMT2A inhibitors has shown significant promise in treating relapsed or refractory acute leukemias, though challenges such as differentiation syndrome and the emergence of resistance mutations in the Menin binding site remain areas of active investigation.

Other names

Menin-MLL1 interactionMenin-MLL protein-protein interactionMEN1-KMT2A complexMenin-Mixed Lineage Leukemia interaction

Small molecule inhibition of the Menin-KMT2A binding interface, which displaces the KMT2A fusion protein or wild-type KMT2A from the Menin complex, leading to the downregulation of leukemogenic genes such as HOXA9 and MEIS1 and inducing myeloid differentiation.