DOT1L

DOT1L, named for disruptor of telomeric silencing 1-like, is a histone methyltransferase that catalyzes the methylation of lysine 79 on histone H3 (H3K79). It is a non-SET-domain enzyme functioning in the nucleus to deposit mono-, di-, and tri-methyl marks on H3K79, a modification found within the globular domain of histone H3 and associated with active transcription. The enzyme uses S-adenosyl-L-methionine as a methyl donor and participates in multiple chromatin-modifying complexes that regulate gene expression and chromatin structure.

Biological roles of DOT1L include links between H3K79 methylation and transcriptional elongation, with enrichment at actively transcribed gene bodies. It also contributes to genome stability and the DNA damage response. In vertebrates, DOT1L is required for development and hematopoiesis, and perturbation of its activity can affect cell proliferation and differentiation, reflecting broad roles in chromatin regulation beyond single pathways.

In disease, DOT1L is a key player in leukemias with mixed lineage leukemia (MLL) gene fusions. In these cancers, MLL fusion proteins recruit DOT1L to aberrant target genes, leading to sustained expression of leukemogenic programs such as HOXA9 and MEIS1. This mechanism makes DOT1L a therapeutic target in MLL-rearranged leukemia, with the aim of reducing pathological H3K79 methylation and downstream gene expression.

Therapeutics and research efforts include small-molecule inhibitors of DOT1L, notably pinometostat (EPZ-5676), which have been evaluated in clinical trials for MLL-rearranged leukemias. Inhibition lowers H3K79 methylation and disrupts leukemogenic transcription, with ongoing studies to determine efficacy, optimal combinations, and potential effects on normal physiology.