Menin-Mixed Lineage Leukemia 1 (Menin-MLL1) protein-protein interaction (Menin-MLL PPI)

The Menin-Mixed Lineage Leukemia (Menin-MLL) protein-protein interaction is a pivotal epigenetic regulatory node that plays a central role in the development of specific aggressive leukemias. Menin, a scaffold protein encoded by the MEN1 gene, binds to the N-terminus of the Mixed Lineage Leukemia 1 (MLL1, also known as KMT2A) protein, facilitating the assembly of a chromatin-modifying complex (Yokoyama et al., 2005, Cell). In leukemias harboring MLL rearrangements (MLL-r) or NPM1 mutations, this interaction is required to maintain the expression of homeobox genes like HOXA9 and MEIS1, which block hematopoietic differentiation and promote leukemic cell survival (Krivtsov & Armstrong, 2007, Nature Reviews Cancer). Therapeutic strategies focus on small-molecule inhibitors that bind to the Menin pocket, preventing its association with MLL fusion proteins or wild-type MLL. This disruption results in the rapid downregulation of the leukemogenic transcriptional program, inducing cell cycle arrest and myeloid differentiation (Issa et al., 2023, Nature). Clinical trials of Menin inhibitors, such as revumenib and ziftomenib, have demonstrated promising clinical activity in relapsed or refractory acute leukemias, although clinicians must monitor for differentiation syndrome and potential QTc prolongation (Erba et al., 2023, ASH Annual Meeting).

Other names

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

Small molecule inhibition of the protein-protein interaction between Menin and the N-terminal fragment of MLL1 (KMT2A) or MLL-fusion proteins, leading to the displacement of the MLL complex from chromatin and subsequent transcriptional repression of oncogenic targets like HOXA9 and MEIS1 (Yokoyama et al., 2005, Cell; Issa et al., 2023, Nature).