ArticleThe Journal of biological chemistry2013
Targeting recruitment of disruptor of telomeric silencing 1-like (DOT1L): characterizing the interactions between DOT1L and mixed lineage leukemia (MLL) fusion proteins.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 38 citations in OpenAlex.
- Acetylation-independent mechanism for binding of ENL to intrinsically disordered regions in TAF2/6 and SNF5.Nucleic acids research · 2026Article
- Discovery of a Highly Potent and Selective ENL Degrader.Journal of medicinal chemistry · 2026Article
- Targeting the Menin-KMT2A interaction in leukemia: Lessons learned and future directions.International journal of cancer · 2026Review
- DOT1L as a Therapeutic Target: Insights into Epigenetic Regulation and Cancer Treatment.Biomolecules & therapeutics · 2025Review
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Functional Roles and Mechanistic Insights of YEATS Domain Proteins in Digestive System Tumors.Digestive diseases and sciences · 2025Review
- A multivalent engagement of ENL with MOZ.Nature structural & molecular biology · 2025Article
- Rational design of small-sized peptidomimetic inhibitors disrupting protein-protein interaction.RSC medicinal chemistry · 2024Review
- Structural studies of intrinsically disordered MLL-fusion protein AF9 in complex with peptidomimetic inhibitors.Protein science : a publication of the Protein Society · 2024Article
- The YEATS domain epigenetic reader proteins ENL and AF9 and their therapeutic value in leukemia.Experimental hematology · 2023Review
- The ENL YEATS epigenetic reader domain critically links MLL-ENL to leukemic stem cell frequency in t(11;19) Leukemia.Leukemia · 2023Article
- Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias.Journal of hematology & oncology · 2022Review
- Multifaceted roles of YEATS domain-containing proteins and novel links to neurological diseases.Cellular and molecular life sciences : CMLS · 2022Review
- Emerging Targeted Therapy for Specific Genomic Abnormalities in Acute Myeloid Leukemia.International journal of molecular sciences · 2022Review
- The Role of DOT1L in Normal and Malignant Hematopoiesis.Frontiers in cell and developmental biology · 2022Review
- Structure, function and inhibition of critical protein-protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins.Journal of hematology & oncology · 2021Review
- Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis.Cancers · 2021Article
- Identification of DOT1L inhibitors by structure-based virtual screening adapted from a nucleoside-focused library.European journal of medicinal chemistry · 2020Article
- The mechanism of MYB transcriptional regulation by MLL-AF9 oncoprotein.Scientific reports · 2019Article
- Molecular characterization of an MLL1 fusion and its role in chromosomal instability.Molecular oncology · 2019Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). Here we report biochemical, biophysical, and functional characterization of the interaction between DOT1L and MLL fusion proteins, AF9/ENL. The AF9/ENL-binding site in human DOT1L was mapped, and the interaction site was identified to a 10-amino acid region (DOT1L865-874). This region is highly conserved in DOT1L from a variety of species. Alanine scanning mutagenesis analysis shows that four conserved hydrophobic residues from the identified binding motif are essential for the interactions with AF9/ENL. Binding studies demonstrate that the entire intact C-terminal domain of AF9/ENL is required for optimal interaction with DOT1L. Functional studies show that the mapped AF9/ENL interacting site is essential for immortalization by MLL-AF9, indicating that DOT1L interaction with MLL-AF9 and its recruitment are required for transformation by MLL-AF9. These results strongly suggest that disruption of interaction between DOT1L and AF9/ENL is a promising therapeutic strategy with potentially fewer adverse effects than enzymatic inhibition of DOT1L for MLL fusion protein-associated leukemia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.