DOT1L is a histone lysine methyltransferase that catalyzes methylation of lysine 79 on histone H3, a modification distinct from those catalyzed by SET-domain-containing methyltransferases 1. The enzyme preferentially methylates nucleosomal histones over free histone substrates and contains a unique non-SET catalytic domain with a SAM-binding pocket and a positively charged C-terminal region critical for nucleosome engagement 2. DOT1L participates in multiple biological processes including transcriptional regulation, DNA damage checkpoint signaling, and telomere organization. DOT1L's clinical significance has emerged primarily through its role in hematologic malignancies. In MLL-rearranged leukemia, DOT1L cooperates with the AF4-containing complex to aberrantly activate transcription of oncogenic targets 3. In diffuse large B-cell lymphoma and follicular lymphoma, combined inhibition of DOT1L and EZH2 synergistically suppresses cell cycle genes, enhances interferon signaling, and drives B-cell differentiation, showing preclinical efficacy in xenograft models 4. Recent evidence suggests DOT1L also mediates acquired resistance to PARP inhibitors in ovarian cancer by regulating drug efflux and survival pathways; combined DOT1L and PARP inhibitor treatment shows synergistic effects in cell-derived models and patient-derived organoids 5. These findings establish DOT1L inhibition as a promising therapeutic strategy across multiple cancer types, particularly when combined with other epigenetic or targeted agents.