Menin–Mixed Lineage Leukemia (MLL) protein–protein interaction (Menin–MLL PPI)

The menin–Mixed Lineage Leukemia (MLL) protein–protein interaction is a critical epigenetic regulatory mechanism frequently co-opted in aggressive forms of leukemia (Yokoyama et al., 2005, PubMed: 15964828). Menin, a scaffold protein encoded by the MEN1 gene, binds to the N-terminus of MLL1 (KMT2A) or MLL fusion proteins, facilitating the recruitment of the MLL complex to specific genomic loci (Grembecka et al., 2012, PubMed: 22234154). This interaction is essential for the constitutive expression of pro-leukemogenic genes, including the HOXA cluster and MEIS1, which block hematopoietic differentiation and drive leukemic transformation (Krivtsov & Armstrong, 2007, PubMed: 17957201). In patients with MLL rearrangements (MLL-r) or NPM1 mutations, this complex becomes a primary driver of the disease. Therapeutic targeting involves small-molecule inhibitors that occupy the MLL-binding pocket on menin, effectively disrupting the complex and inducing cell cycle arrest and myeloid differentiation (Issa et al., 2023, PubMed: 36922593). Clinical trials have demonstrated significant efficacy for these inhibitors in relapsed or refractory acute leukemias, though challenges such as differentiation syndrome and the emergence of resistance mutations in the MEN1 gene remain areas of active investigation (Perner et al., 2023, PubMed: 36922591).

Other names

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

Small-molecule inhibition of the menin–MLL interaction, which displaces the MLL-fusion protein or wild-type MLL from the HOXA and MEIS1 gene promoters, leading to transcriptional repression of these leukemogenic drivers and subsequent induction of myeloid differentiation and apoptosis (Grembecka et al., 2012, PubMed: 22234154; Issa et al., 2023, PubMed: 36922593).