title: The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO.
abstract: The chromosomal translocation (8;21) fuses the hematopoietic transcription factor AML1 (RUNX1) with ETO (RUNX1T1, MTG8), resulting in the leukemia-specific chimeric protein AML1/ETO. This fusion protein has been implicated in epigenetic silencing, recruiting histone deacetylases (HDACs) and DNA methyltransferases to target promoters. Previously, we have identified a novel in vivo AML1/ETO target gene, LAT2 (NTAL/LAB/WBSCR5), which is involved in FcɛR I, c-Kit, B-cell and T-cell receptor signalling. We have now addressed the molecular mechanisms of AML1/ETO-mediated LAT2 repression. In Kasumi-1 cells, where AML1/ETO bound to the LAT2 gene, small interfering RNA (siRNA)-mediated AML1/ETO depletion caused upregulation of LAT2, suggesting a possible direct mechanism of repression. Expression of AML1/ETO was associated with a decrease in acetylation of histones H3, H3K9 and H4, and an increase in H3K9 and H3K27 trimethylation. The class I-specific HDAC inhibitors entinostat (MS-275) and mocetinostat (MGCD0103) induced LAT2 expression specifically in AML1/ETO-expressing cells, resulting in induction of several activating histone marks on the LAT2 gene, including trimethylation of histone H3K4. The combination of entinostat and decitabine increased acetylation of histones H3 and H4, as well as LAT2 mRNA expression, in an at least additive fashion. In conclusion, several repressive histone modifications mark the LAT2 gene in the presence of AML1/ETO, and LAT2 gene derepression is achieved by pharmacological inhibition of HDACs.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Freiburg, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Duque-Afonso
authors.forename: A
authors.initials: A
authors.lastname: Yalcin
authors.forename: T
authors.initials: T
authors.lastname: Berg
authors.forename: M
authors.initials: M
authors.lastname: Abdelkarim
authors.forename: O
authors.initials: O
authors.lastname: Heidenreich
authors.forename: M
authors.initials: M
authors.lastname: Lübbert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001549:Benzamides / Q000494:pharmacology*; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008745:Methylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit; D056572:Histone Deacetylase Inhibitors; C419196:LAT2 protein, human; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; C118739:entinostat