Menin–Lysine Methyltransferase 2A (KMT2A) protein–protein complex (Menin–KMT2A complex)

The Menin–Lysine Methyltransferase 2A (KMT2A) protein–protein complex is a critical epigenetic regulatory assembly that plays a pivotal role in gene transcription and hematopoietic development. Menin, a scaffold protein encoded by the MEN1 gene, binds to the amino-terminus of KMT2A (formerly MLL1) to facilitate the recruitment of chromatin-modifying complexes to specific gene loci [UniProt: O00255, Q03164]. In leukemias characterized by KMT2A rearrangements (KMT2Ar) or NPM1 mutations, this interaction becomes a dependency for the survival of malignant cells, as it drives the overexpression of oncogenic transcription factors such as HOXA9 and MEIS1 [PubMed: 28434989]. By maintaining these genes in an active state, the complex prevents the differentiation of hematopoietic progenitors, leading to the accumulation of leukemic blasts. Small-molecule inhibitors have been developed to specifically disrupt the Menin–KMT2A interface by occupying the binding pocket on Menin [PubMed: 36922593]. This therapeutic intervention results in the rapid downregulation of leukemogenic gene programs and induces the differentiation of leukemia cells into mature lineages. Several inhibitors, including revumenib and ziftomenib, are currently in clinical trials and have demonstrated significant efficacy in patients with relapsed or refractory acute myeloid leukemia [ClinicalTrials.gov: NCT04065399, NCT04067336]. Resistance to these therapies can emerge through acquired mutations in the MEN1 gene that prevent drug binding while preserving the interaction with KMT2A [PubMed: 36922593].

Other names

Menin–MLL1 complexMenin–MLL complexMenin–KMT2A interactionMEN1–KMT2A complex

Disruption of the protein-protein interaction between Menin and KMT2A (or KMT2A-fusion proteins), leading to transcriptional repression of oncogenic targets like HOXA and MEIS1.