KMT2D (lysine methyltransferase 2D) is a histone methyltransferase that catalyzes monomethylation of histone H3 at lysine 4 (H3K4me1) 1, a chr12 mark associated with active gene enhancers and transcriptional regulation sites 21. KMT2D functions within chr12 remodeling complexes, including phase-separated liquid condensates that concentrate its enzymatic activity 3. It acts as a coactivator for estrogen receptor-driven transcription by priming gene enhancer regions 45. Pathogenic KMT2D variants cause Kabuki syndrome, a developmental disorder characterized by hypotonia, developmental delay, distinctive facial dysmorphism, cardiac and renal anomalies, occurring in ~75% of cases 67. Beyond developmental disease, KMT2D functions as a tumor suppressor, with frequent mutations in multiple cancers: 10-20% of breast cancers 5, >20% of lung squamous cell carcinomas 8, and acute myeloid leukemias 9. KMT2D loss drives tumorigenesis through chr12 reprogramming; in lung cancer, deficiency increases RTK-RAS signaling and renders tumors vulnerable to RTK pathway inhibition 8. In AML, KMT2D loss activates mTOR signaling and enhances ribosome biogenesis, creating vulnerability to RNA polymerase I inhibitors 9.