ArticleNature medicine2015
DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia.
Article in Nature medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 144 papers.
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144 citing papers in PubMed, 249 citations in OpenAlex.
- Menin Inhibition in Acute Myeloid Leukemia: Rewiring Leukemic Transcriptional Networks.International journal of molecular sciences · 2026Review
- Review
- The Histone Methyltransferase KMT2D Is a Critical Mediator of Lineage Plasticity and Therapeutic Response in Castration-Resistant Prostate Cancer.Cancer research · 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
- KMT2A-rearranged leukemia: from mechanism to drug development.Experimental hematology · 2025Review
- The Inositol-5-Phosphatase SHIP1: Expression, Regulation and Role in Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2025Review
- Transcriptomic characterisation of acute myeloid leukemia cell lines bearing the same t(9;11) driver mutation reveals different molecular signatures.BMC genomics · 2025Article
- The Role of the Sirtuin Family Histone Deacetylases in Acute Myeloid Leukemia-A Promising Road Ahead.Cancers · 2025Review
- DOT1L Mediates Stem Cell Maintenance and Represents a Therapeutic Vulnerability in Cancer.Cancer research · 2025Review
- Fusion-specific chromatin profiles mediate transcriptional heterogeneity in MLL-rearranged acute lymphoblastic leukemia.Blood advances · 2025Article
- Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions.Cancers · 2024Review
- MLL oncoprotein levels influence leukemia lineage identities.Nature communications · 2024Article
- Recent Developments and Evolving Therapeutic Strategies in KMT2A-Rearranged Acute Leukemia.Cancer medicine · 2024Review
- Application of omics in the diagnosis, prognosis, and treatment of acute myeloid leukemia.Biomarker research · 2024Review
- Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery.Science advances · 2024Article
- RNA-binding protein RBM5 plays an essential role in acute myeloid leukemia by activating the oncogenic protein HOXA9.Genome biology · 2024Article
- Immunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia.Molecular cancer · 2023Article
- Microglial SIRT1 activation attenuates synapse loss in retinal inner plexiform layer via mTORC1 inhibition.Journal of neuroinflammation · 2023Article
- Gain-of-function mutations in the catalytic domain ofScience advances · 2023Article
84 more citing papers are in PubMed but not listed here.
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17 authors at 5 institutions in 1 country.
Funding
Abstract
Rearrangements of MLL (encoding lysine-specific methyltransferase 2A and officially known as KMT2A; herein referred to as MLL to denote the gene associated with mixed-lineage leukemia) generate MLL fusion proteins that bind DNA and drive leukemogenic gene expression. This gene expression program is dependent on the disruptor of telomeric silencing 1-like histone 3 lysine 79 (H3K79) methyltransferase DOT1L, and small-molecule DOT1L inhibitors show promise as therapeutics for these leukemias. However, the mechanisms underlying this dependency are unclear. We conducted a genome-scale RNAi screen and found that the histone deacetylase SIRT1 is required for the establishment of a heterochromatin-like state around MLL fusion target genes after DOT1L inhibition. DOT1L inhibits chromatin localization of a repressive complex composed of SIRT1 and the H3K9 methyltransferase SUV39H1, thereby maintaining an open chromatin state with elevated H3K9 acetylation and minimal H3K9 methylation at MLL fusion target genes. Furthermore, the combination of SIRT1 activators and DOT1L inhibitors shows enhanced antiproliferative activity against MLL-rearranged leukemia cells. These results indicate that the dynamic interplay between chromatin regulators controlling the activation and repression of gene expression could provide novel opportunities for combination therapy.
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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.