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The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO.
Oncogene 2011; 30(27):3062-72O

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+Show Affiliations

Department of Medicine, Division of Hematology/Oncology, University of Freiburg, University Medical Center Freiburg, Freiburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21577204

Citation

Duque-Afonso, J, et al. "The HDAC Class I-specific Inhibitor Entinostat (MS-275) Effectively Relieves Epigenetic Silencing of the LAT2 Gene Mediated By AML1/ETO." Oncogene, vol. 30, no. 27, 2011, pp. 3062-72.
Duque-Afonso J, Yalcin A, Berg T, et al. The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO. Oncogene. 2011;30(27):3062-72.
Duque-Afonso, J., Yalcin, A., Berg, T., Abdelkarim, M., Heidenreich, O., & Lübbert, M. (2011). The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO. Oncogene, 30(27), pp. 3062-72. doi:10.1038/onc.2011.32.
Duque-Afonso J, et al. The HDAC Class I-specific Inhibitor Entinostat (MS-275) Effectively Relieves Epigenetic Silencing of the LAT2 Gene Mediated By AML1/ETO. Oncogene. 2011 Jul 7;30(27):3062-72. PubMed PMID: 21577204.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO. AU - Duque-Afonso,J, AU - Yalcin,A, AU - Berg,T, AU - Abdelkarim,M, AU - Heidenreich,O, AU - Lübbert,M, Y1 - 2011/05/16/ PY - 2011/5/18/entrez PY - 2011/5/18/pubmed PY - 2011/9/16/medline SP - 3062 EP - 72 JF - Oncogene JO - Oncogene VL - 30 IS - 27 N2 - 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. SN - 1476-5594 UR - https://www.unboundmedicine.com/medline/citation/21577204/The_HDAC_class_I_specific_inhibitor_entinostat__MS_275__effectively_relieves_epigenetic_silencing_of_the_LAT2_gene_mediated_by_AML1/ETO_ L2 - http://dx.doi.org/10.1038/onc.2011.32 DB - PRIME DP - Unbound Medicine ER -