The Histone-Lysine N-Methyltransferase (KMT2) Family in Health and Disease.

The histone-lysine N-methyltransferase (KMT2) family is a central epigenetic regulator whose dysfunction drives diverse human diseases through distinct molecular mechanisms. In acute leukemias, KMT2A rearrangements aberrantly recruit transcriptional cofactors, activating oncogenic gene programs; in solid tumors, loss-of-function mutations in KMT2C/D disrupt enhancer-mediated regulatory networks, compromising cellular identity and genome stability; in neurodevelopmental disorders, germline haploinsufficiency of KMT2A/B/D impairs developmental epigenetic programming. Despite increasingly comprehensive understanding of the pathogenic mechanisms involving KMT2 family members, a unified framework translating these molecular insights into effective, subtype-specific therapeutic strategies has been lacking. This review comprehensively deconstructs these pathogenic pathways and explores how mechanistic insights are being translated into novel therapeutic strategies, including direct targeting of oncogenic transcriptional complexes,  exploiting vulnerabilities from tumor suppressor loss, and modulating the tumor immune microenvironment. We systematically synthesize recent clinical advances, from small-molecule inhibitors against protein-protein interactions (e.g., menin-KMT2A), to targeted degraders (PROTACs), epigenetic readers/writers inhibitors (e.g., BET, LSD1, DOT1L), and rational combination regimens with chemotherapy or immunotherapy. By integrating the biological characteristics of KMT2 with translational medicine and clinical evidence, this study provides a framework for advancing precision medicine approaches based on the molecular subtypes driven by KMT2.