The signaling upstream of DOT1L-mediated H3K79 methylation.

Histone lysine methylation is a post-translational modification system that has a profound impact on gene expression. The methylation of H3K79 plays an important role in gene transcription, repair of DNA damage, and cell cycle. In recent years, it has been discovered that Disruptor of telomeric silencing 1-like (DOT1L) can methylate H3K79 and is the only known H3K79 methyltransferase. DOT1L activity in leukemia cells interacts with ubiquitinated H2B to promote nucleosome binding. AF family proteins bind DNA to ENL to recruit DOT1L to the promoters of KMT2A (formerly MLL1)-rearranged leukemia target genes, promoting HOXA9 overexpression, a key event in leukemia. Moreover, DOT1L O-GlcNAcylation promotes its protein stability and proliferation of MLL fusion leukemia cells. This review summarizes the structure, biological functions and upstream regulatory mechanisms of DOT1L-mediated H3K79 methylation. Relevant literature was searched in PubMed and Web of Science for studies published from 2000 to 2024 using keywords including "DOT1L," "H3K79 methylation" and "KMT2A leukemia."