{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DOT1L is an evolutionarily conserved histone methyltransferase that exclusively catalyzes methylation of lysine 79 on histone H3 (H3K79), an epigenetic mark strongly associated with actively transcribed chromatin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Structural and biochemical studies have revealed that DOT1L’s catalytic activity is modulated by upstream events such as histone H2B monoubiquitination, which induces allosteric changes in the nucleosome to permit efficient H3K79 methylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In normal cells, DOT1L is recruited to the proximal transcribed regions of active genes—often via interactions with chromatin-associated factors including members of the Dot1 complex (DotCom) and proteins harboring YEATS domains—thereby facilitating transcriptional elongation and maintaining proper gene expression and chromatin structure during development and hematopoiesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Aberrant targeting or hyperactivation of DOT1L, however, plays a pivotal role in oncogenesis. In several leukemias driven by mixed-lineage leukemia (MLL) fusion proteins, DOT1L is erroneously recruited to fusion target loci, resulting in excessive H3K79 methylation and sustained activation of critical oncogenes such as HOX genes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": " Similar mistargeting mechanisms underlie the leukemogenic transformation observed in models of MLL-rearranged acute lymphoblastic leukemia and mixed-lineage leukemia, where DOT1L dependency is critical for both initiation and maintenance of the malignant gene expression program. Moreover, beyond its established role in hematologic malignancies, DOT1L has emerged as an important mediator of oncogenic transcription in solid tumors. For instance, in prostate and breast cancers, DOT1L is co-opted—via interactions with transcription factors and coactivators such as c-Myc/p300—to activate epithelial–mesenchymal transition regulators, thereby promoting tumor aggressiveness and stem-like properties."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight DOT1L as a central mediator bridging chromatin modifications with transcriptional regulation. Its precise recruitment by different protein partners under normal physiological conditions ensures proper gene expression, while its dysregulation leads to the misactivation of oncogenic programs in leukemia and other cancers. As such, DOT1L and its associated regulatory pathways represent attractive targets for therapeutic intervention in DOT1L-dependent malignancies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kathrin M Bernt, Nan Zhu, Amit U Sinha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2011.06.010"}], "href": "https://doi.org/10.1016/j.ccr.2011.06.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21741597"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21741597"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "David J Steger, Martina I Lefterova, Lei Ying, et al. 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