Menin (MEN1) (MEN1)

Menin is a scaffold protein encoded by the MEN1 gene that plays a pivotal role in epigenetic regulation by interacting with the N-terminus of Lysine Methyltransferase 2A (KMT2A, also known as MLL1) [UniProt, O00255]. This interaction is essential for the recruitment of the KMT2A complex to target genes, such as the HOXA cluster and MEIS1, which are critical for normal hematopoiesis [PubMed, 26000447]. In specific leukemias, including those with KMT2A rearrangements or NPM1 mutations, the menin-KMT2A complex is constitutively active, driving the overexpression of these oncogenic factors and blocking myeloid differentiation [Nature, 2023, 615(7954)]. Therapeutic agents known as menin inhibitors, such as revumenib and ziftomenib, are designed to bind to the menin protein and competitively disrupt its interface with KMT2A [NEJM, 2023, 389(11)]. By breaking this protein-protein interaction, these drugs induce the downregulation of leukemogenic transcription programs, leading to cell cycle arrest and terminal differentiation of leukemic blasts [Cancer Discovery, 2020, 10(9)]. This target represents a significant breakthrough in precision medicine for acute myeloid and lymphoblastic leukemias [Blood, 2022, 140(Supplement 1)].

Other names

MEN1Multiple endocrine neoplasia type 1 proteinSCG2MEAI

Small molecule inhibition of the protein-protein interaction (PPI) between menin and the N-terminus of KMT2A (MLL1), preventing the formation of the menin-KMT2A complex and subsequent transcription of oncogenic genes.