DOTIL drives the progression of multiple cancers, such as MLL-r leukemia,718 renal cell carcinoma,719 ovarian cancer,720 and breast cancer.721 DOT1L-mediated H3K79 methylation promotes transcriptional elongation and/or enhancer-promoter interaction,722 which is hijacked by oncogenic transcription factors, such as MLL-fusion proteins in MLL-r leukemia718 and estrogen receptor α in breast cancer,721 to activate downstream target genes. This evidence concerns the gene ESR1 and breast cancer.