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

The menin–KMT2A protein-protein interaction is a pivotal epigenetic mechanism involved in the pathogenesis of specific genetically defined leukemias (Krivtsov & Armstrong, 2007; PMID: 17235351). Menin, a scaffold protein encoded by the MEN1 gene, binds to the N-terminal region of Lysine Methyltransferase 2A (KMT2A, formerly MLL1) to regulate the transcription of genes essential for hematopoiesis (Yokoyama et al., 2005; PMID: 15964828). In leukemias harboring KMT2A rearrangements (KMT2Ar) or NPM1 mutations, the menin–KMT2A complex constitutively activates the expression of homeobox genes like HOXA9 and MEIS1, which arrest myeloid differentiation and drive leukemogenesis (Kura Oncology, 2024; Syndax Pharmaceuticals, 2024). Small molecule inhibitors target the menin–KMT2A interface by binding to the menin pocket, effectively displacing KMT2A or its fusion proteins from the chromatin (Issa et al., 2023; PMID: 36922593). This pharmacological disruption results in the loss of the oncogenic transcriptional program and promotes the terminal differentiation of leukemic cells (Erba et al., 2022; PMID: 38359354). Currently, several menin inhibitors are in clinical trials, demonstrating significant efficacy in patients with relapsed or refractory acute myeloid leukemia and acute lymphoblastic leukemia.

Other names

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

Small molecule inhibition of the protein-protein interaction between the scaffold protein menin and the N-terminal fragment of lysine methyltransferase 2A (KMT2A/MLL1).