[Chiba Medical Society Award Review]Beyond histone modification: non-catalytic functions of epigenomic enzymes in leukemia progression

[ABSTRACT]Histone methylation is an extensively characterized epigenetic modification tightly linked to transcriptional regulation. In leukemia, the genome-wide distribution and abundance of H3K4 trimethylation (H3K4me3) correlate with the leukemia-initiating cell population, particularly in the KMT2A-rearranged acute myelogenous leukemia (AML) model. KMT2A, a member of the H3K4 methyltransferase family, is a well-established driver of leukemogenesis, and genetic alterations or oncogenic fusions critically contribute to disease onset and progression. Traditionally, the pathogenic functions of these enzymes have been attributed to their catalytic activity. However, accumulating evidence indicates that KMT2A and other H3K4me3 methyltransferases promote leukemia progression through non-catalytic mechanisms. These include scaffolding functions that organize transcriptional complexes and regulate cellular metabolism independent of histone modification. This review summarizes the current knowledge on the non-catalytic functions of H3K4 methyltransferases, with a focus on KMT2A and related proteins, SETD1A/B, and discusses how targeting these mechanisms may provide novel opportunities for leukemia therapy.