Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L‐dose dependency in HDAC1‐deficient thymic lymphoma

• Hanneke Vlaming ^[1] ; Chelsea M McLean ^[2] ; Tessy Korthout ^[2] ; Mir Farshid Alemdehy ^[3] ; Sjoerd Hendriks ^[2] ; Cesare Lancini ^[2] ; Sander Palit ^[2] ; Sjoerd Klarenbeek ^[4] ; Eliza Mari Kwesi‐Maliepaard ^[2] ; Thom M Molenaar ^[2] ; Liesbeth Hoekman ^[4] ; Thierry T Schmidlin ^[5] ; AF Maarten Altelaar ^[6] ; Tibor van Welsem ^[2] ; Jan‐Hermen Dannenberg ^[7] ; Heinz Jacobs ^[3] ; Fred van Leeuwen ^[2]
  1. [1] 1 Division of Gene Regulation Netherlands Cancer Institute Amsterdam The Netherlands; 6Present address: Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School Boston MA USA
  2. [2] 1 Division of Gene Regulation Netherlands Cancer Institute Amsterdam The Netherlands
  3. [3] 2 Division of Tumor Biology & Immunology Netherlands Cancer Institute Amsterdam The Netherlands
  4. [4] 3 Experimental Animal Pathology Netherlands Cancer Institute Amsterdam The Netherlands
  5. [5] 4 Biomolecular Mass Spectrometry and Proteomics Bijvoet Center for Biomolecular Research Utrecht Institute for Pharmaceutical Sciences Utrecht University and Netherlands Proteomics Centre Utrecht The Netherlands
  6. [6] 4 Biomolecular Mass Spectrometry and Proteomics Bijvoet Center for Biomolecular Research Utrecht Institute for Pharmaceutical Sciences Utrecht University and Netherlands Proteomics Centre Utrecht The Netherlands; 5 Proteomics Facility Netherlands Cancer Institute Amsterdam The Netherlands
  7. [7] 1 Division of Gene Regulation Netherlands Cancer Institute Amsterdam The Netherlands; 7Present address: Genmab B.V. Antibody Sciences Utrecht The Netherlands

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 14, 2019
• Idioma: inglés
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  • DOT1L methylates histone H3K79 and is aberrantly regulated in MLL‐rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1. At its target genes, the transcriptional repressor Rpd3 restricts H3K79 methylation, explaining the absence of H3K79me3 at a subset of genes in the yeast genome. Similar to the crosstalk in yeast, inactivation of the murine Rpd3 homolog HDAC1 in thymocytes led to an increase in H3K79 methylation. Thymic lymphomas that arise upon genetic deletion of Hdac1 retained the increased H3K79 methylation and were sensitive to reduced DOT1L dosage. Furthermore, cell lines derived from Hdac1 Δ/Δ thymic lymphomas were sensitive to a DOT1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between HDAC1 and DOT1L with impact in murine thymic lymphoma development.