Kmt2d, also known as MLL4 and MLL2 in humans and Mll4 in mice, belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein, partially functionally redundant with KMT2C, and widely expressed in adult tissues, being essential for early embryonic development. Kmt2d associates with multiple proteins in a complex, acts as a scaffold, and is crucial for maintaining the stability of UTX. It is a major H3K4 mono-methyltransferase, co-localizes with lineage-determining transcription factors on transcriptional enhancers, and is required for enhancer activation and cell-type specific gene expression. Kmt2d plays critical roles in regulating development, differentiation, metabolism, and tumor suppression [2].

In lung cancer, lung-specific Kmt2d knockout promotes tumorigenesis in mice. Kmt2d deletion in lung basal cell organoids transforms them to lung squamous cell carcinoma (LUSC). Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), such as EGFR and ERBB2, through chromatin reprogramming to repress protein tyrosine phosphatases, enhancing the oncogenic RTK-RAS signaling. Combining SHP2 and pan-ERBB inhibitors can inhibit lung tumor growth in Kmt2d-deficient LUSC murine models and patient-derived xenografts with KMT2D mutations. Also, Kmt2d deficiency upregulates pro-tumorigenic programs like glycolysis, making cells with KMT2D-inactivating mutations vulnerable to glycolytic inhibitors [1,3]. In myeloid leukemias, Kmt2d deficiency accelerates leukemogenesis in mice. Hematopoietic stem and progenitor cells and AML cells with Kmt2d loss have enhanced ribosome biogenesis due to mTOR pathway activation, as Kmt2d directly regulates Ddit4, a negative regulator of mTOR. The inhibitor of RNA polymerase I, CX-5461, restrains the growth of AML with Kmt2d loss in vivo [4]. In triple-negative breast cancer murine models, deletion of Kmt2d drives metastasis, especially to the brain, through epigenetic upregulation of Mmp3 via enhanced binding of KDM6A [5].

In conclusion, Kmt2d is a key epigenetic regulator essential for normal development and has a tumor-suppressive role. Gene knockout and conditional knockout mouse models have been crucial in revealing its role in various disease conditions, such as different types of cancers. These findings highlight the potential of targeting pathways affected by Kmt2d deficiency for therapeutic interventions.