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    GENE:

    DOT1L (DOT1 Like Histone Lysine Methyltransferase)

    i
    Other names: DOT1L, DOT1 Like Histone Lysine Methyltransferase, KMT4, Histone-Lysine N-Methyltransferase, H3 Lysine-79 Specific, Histone H3-K79 Methyltransferase, Histone Methyltransferase DOT1L, Lysine N-Methyltransferase 4, DOT1-Like Protein, H3-K79-HMTase, DOT1-Like, Histone H3 Methyltransferase (S. Cerevisiae), DOT1 Like Histone H3K79 Methyltransferase, DOT1-Like, Histone H3 Methyltransferase, DOT1-Like Histone Methyltransferase
    10d
    Development of DOT1L-Targeted Protein Degraders for Treating MLL-r Leukemia. (PubMed, J Med Chem)
    Substantial previous work has developed catalytic inhibitors like pinometostat, which showed limited clinical efficacy...In vivo studies with DOT1L808 showed its ability to achieve complete tumor regression in an orthotopic leukemia model without overt toxicity. These results establish protein degradation as a promising therapeutic strategy for MLL-rearranged leukemias.
    Journal
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    DOT1L (DOT1 Like Histone Lysine Methyltransferase)
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    pinometostat (EPZ-5676)
    19d
    DOT1L provides transcriptional memory through PRC1.1 antagonism. (PubMed, Nat Cell Biol)
    This regulatory crosstalk is conserved across cell types and is driven by direct biochemical antagonism between H3K79 methylation and PRC1 activity. Together, our findings establish DOT1L as a component of transcriptional memory co-opted in leukaemia and suggest it serves as the missing link balancing the opposing forces of the MLL-Polycomb axis.
    Journal
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    DOT1L (DOT1 Like Histone Lysine Methyltransferase)
    23d
    Identification of LncRNAs scaffolding a chromatin-associated gene regulatory complex in breast cancer cells comprising ERα, DOT1L and menin. (PubMed, Cell Commun Signal)
    Many of deregulated genes were directly bound by all three proteins, suggesting a coordinated transcriptional regulation, revealing a critical axis involving ERα, DOT1L, menin and PVT1. Targeting this RNA-dependent chromatin associated regulatory complex could offer novel therapeutic strategies for BC treatment.
    Journal
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    ER (Estrogen receptor) • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • PVT1 (Pvt1 Oncogene)
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    ER positive
    24d
    Research Progress on the KMT2A-AFF3 Fusion Gene in Childhood Acute Lymphoblastic Leukemia: Mechanisms, Clinical Implications, and Therapeutic Strategies. (PubMed, Curr Issues Mol Biol)
    This review highlights the evidence defining its poor prognosis, which is primarily driven by profound chemoresistance to conventional therapies, including glucocorticoids. Finally, we discuss the rapidly evolving therapeutic landscape, detailing the limitations of standard intensive chemotherapy and the immense promise of novel targeted strategies, such as Menin inhibitors (e.g., Revumenib), DOT1L inhibitors, and immunotherapies (e.g., CAR-T cells, Blinatumomab), which hold the potential to revolutionize outcomes for this high-risk leukemia subtype.
    Review • Journal
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    KMT2A (Lysine Methyltransferase 2A) • AFF1 (AF4/FMR2 Family Member 1) • MEIS1 (Meis Homeobox 1) • MME (Membrane Metalloendopeptidase) • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • AFF3 (AF4/FMR2 Family Member 3)
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    Blincyto (blinatumomab) • Revuforj (revumenib)
    1m
    Extracellular Matrix Stiffness Regulates Cancer Stemness in Uveal Melanoma via the PIEZO1-DOT1L Axis. (PubMed, Invest Ophthalmol Vis Sci)
    The PIEZO1-DOT1L axis mediated ECM stiffness-driven stemness and tumor progression in UM. Targeting this mechanotransduction pathway by modulating ECM stiffness or its downstream effectors may provide a novel therapeutic strategy for UM.
    Journal
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    SOX2 • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • NANOG (Nanog Homeobox)
    1m
    DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. (PubMed, Nat Commun)
    These transcriptional conditions enhance AID occupancy and thereby its activity. Our findings provide a harmonizing explanation for the bidirectional gene expression changes observed in DOT1L-deficient cells, and link attenuated transcriptional elongation velocity and prolonged RNAPII pausing to productive AID engagement at target loci.
    Journal
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    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • DOT1L (DOT1 Like Histone Lysine Methyltransferase)
    1m
    NCI-2017-02296: Testing Olaparib in Patients With Advanced or Metastatic (Cancer That Has Spread) Bladder Cancer and Other Genitourinary Tumors With DNA-Repair Genetic Changes (clinicaltrials.gov)
    P2, N=60, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026
    Trial completion date • Trial primary completion date • Tumor mutational burden
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    TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • ABL1 (ABL proto-oncogene 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • STK11 (Serine/threonine kinase 11) • NPM1 (Nucleophosmin 1) • POLE (DNA Polymerase Epsilon) • CCND1 (Cyclin D1) • BAP1 (BRCA1 Associated Protein 1) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • ATRX (ATRX Chromatin Remodeler) • CHEK2 (Checkpoint kinase 2) • SMARCB1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) • RAD51 (RAD51 Homolog A) • FANCA (FA Complementation Group A) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • POLD1 (DNA Polymerase Delta 1) • CHEK1 (Checkpoint kinase 1) • BARD1 (BRCA1 Associated RING Domain 1) • FANCL (FA Complementation Group L) • BRD4 (Bromodomain Containing 4) • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • FANCE (FA Complementation Group E) • FANCG (FA Complementation Group G) • IKBKE (Inhibitor Of Nuclear Factor Kappa B Kinase Subunit Epsilon) • FANCC (FA Complementation Group C)
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    PALB2 mutation • BRIP1 mutation
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    FoundationOne® CDx • FoundationOne® Liquid CDx
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    Lynparza (olaparib)
    2ms
    Fuzheng Kang'ai Formula suppresses NSCLC by inducing a functional crosstalk between autophagy and ferroptosis via EZH2/DOT1L/H3K79me2 signaling. (PubMed, Phytomedicine)
    FZKA suppresses NSCLC by regulating the EZH2/DOT1L/H3K79me2 signaling to induce crosstalk between mTOR-mediated autophagy and SLC7A11-dependent ferroptosis, leading to extensive cell death. This study reveals a novel epigenetic mechanism coordinating two cell death pathways and supports FZKA's clinical application.
    Journal
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    EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • GPX4 (Glutathione Peroxidase 4) • DOT1L (DOT1 Like Histone Lysine Methyltransferase) • SLC7A11 (Solute Carrier Family 7 Member 11) • BECN1 (Beclin 1)
    2ms
    Histone methyltransferase DOT1L maintains cell state and restricts cytotoxic potential of CD8 T cells. (PubMed, Sci Adv)
    These transcriptional changes were mediated by loss of DOT1L methyltransferase activity in a dose-dependent manner. Our findings show that in mature CD8 T cells, ablation of DOT1L activity is well tolerated and reprograms them to gain innate-like memory cell characteristics and enhance intrinsic cytotoxic capacity.
    Journal
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    CD8 (cluster of differentiation 8) • DOT1L (DOT1 Like Histone Lysine Methyltransferase)
    2ms
    A medicinal chemistry perspective on disruptor of telomeric silencing 1-like: Its mechanisms and modulators in cancer treatment. (PubMed, Eur J Med Chem)
    This review comprehensively summarizes the structure and biological functions of DOT1L, focusing on the research progress of small-molecule modulators, including nucleoside/non-nucleoside inhibitors, protein-protein interaction (PPI) disruptors, dual-target inhibitors, and proteolysis-targeting chimera (PROTAC) molecules, from the perspective of drug design. In addition, this review discusses challenges and future perspectives associated with the discovery of DOT1L-targeted therapies for cancer.
    Review • Journal
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    DOT1L (DOT1 Like Histone Lysine Methyltransferase)
    3ms
    Targeted therapy in KMT2Ar AML. (PubMed, Hematology)
    There is an urgent need for effective targeted drugs for KMT2Ar AML. Continuous research and clinical trials will be key to improving patient prognosis and advancing precise treatment for this challenging leukemia subtype.
    Review • Journal
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    KMT2A (Lysine Methyltransferase 2A) • DOT1L (DOT1 Like Histone Lysine Methyltransferase)
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    KMT2A rearrangement
    3ms
    Inhibition of Methyltransferase DOT1L alleviates anti-tuberculosis drug-induced liver injury by inhibiting p53-Bax/Bcl-2 pathway. (PubMed, Eur J Pharmacol)
    Our findings highlight the importance of DOT1L expression homeostasis in liver physiology and reveal a novel epigenetic mechanism by which DOT1L participates in ADLI progression through transcriptional regulation of p53. These results position DOT1L as a potential therapeutic target for the prevention or treatment of ADLI.
    Journal • IO biomarker
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    BCL2 (B-cell CLL/lymphoma 2) • DOT1L (DOT1 Like Histone Lysine Methyltransferase)