Multiple endocrine neoplasia type 1 protein (Menin) (MEN1)

Menin is a scaffold protein encoded by the MEN1 gene that functions as a critical regulator of gene expression and chromatin remodeling (UniProt O00255). It serves as an essential cofactor for the Lysine Methyltransferase 2A (KMT2A) complex, which mediates histone H3 lysine 4 methylation to promote transcriptional activation (Yokoyama et al., Cell 2005). In certain leukemias, such as those characterized by KMT2A rearrangements or NPM1 mutations, menin is required to tether the oncogenic KMT2A complex to specific gene loci like HOXA9 and MEIS1 (Issa et al., Leukemia 2021). Small-molecule inhibitors have been developed to specifically target the menin-KMT2A protein-protein interface, effectively displacing the KMT2A complex from chromatin and inducing differentiation in leukemic cells (Krivtsov & Armstrong, Nature Reviews Cancer 2007). Clinical-stage inhibitors like revumenib and ziftomenib have demonstrated significant clinical activity in patients with relapsed or refractory acute leukemia (Issa et al., Nature 2023). Despite their therapeutic potential, safety concerns such as differentiation syndrome and the emergence of resistance mutations in the MEN1 gene remain key challenges (Perner et al., Nature 2023).

Other names

MeninMEN1Menin-1Multiple endocrine neoplasia type 1 proteinSCG2

Inhibition of the protein-protein interaction between menin and the KMT2A (MLL1) protein, preventing the recruitment of MLL fusion proteins or wild-type MLL complexes to target gene promoters.