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Blood, 1 September 2008, Vol. 112, No. 5, pp. 2013-2016. Prepublished online as a Blood First Edition Paper on June 19, 2008; DOI 10.1182/blood-2008-01-128595. This Article Full Text (PDF) All Versions of this Article: blood-2008-01-128595v1 112/5/2013    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Whitman, S. P Articles by Caligiuri, M. A Search for Related Content PubMed PubMed Citation Articles by Whitman, S. P Articles by Caligiuri, M. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 9, 2008 Accepted May 28, 2008 DNA hypermethylation and epigenetic silencing of the tumor suppressor gene SLC5A8 in acute myeloid leukemia with the MLL partial tandem duplication Susan P Whitman, Bjoern Hackanson, Sandya Liyanarachchi, Shujun Liu, Laura J Rush, Kati Maharry, Dean Margeson, Ramana Davuluri, Jing Wen, Tatiana Witte, Li Yu, Chunhui Liu, Clara D Bloomfield, Guido Marcucci, Christoph Plass, and Michael A Caligiuri* Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States Department of Hematology-Oncology, University Medical Center, Freiburg, Germany Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, United States Division of Hematology-Oncology, Department of Medicine, The Ohio State University, Columbus, OH, United States Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States Cancer and Leukemia Group B Statistical Center, Duke University, Durham, NC, United States Department of Hematology, Chinese PLA General Hospital, Beijing, China German Cancer Research Center (DKFZ), Heidelburg, Germany * Corresponding author; email: michael.caligiuri{at}osumc.edu. Posttranslationally-modified histones and DNA hypermethylation frequently interplay to deregulate gene expression in cancer. We report that acute myeloid leukemia (AML) with an aberrant histone methyltransferase, the MLL Partial Tandem Duplication (MLL-PTD), exhibits increased global DNA methylation versus AML with MLL-wildtype (MLL-WT) (P=.02). Among the differentially methylated genes, the SLC5A8 tumor suppressor gene (TSG) was more frequently hypermethylated (P=.003). In MLL-PTD+ cell lines having SLC5A8 promoter hypermethylation, incubation with decitabine activated SLC5A8 expression. Ectopic SLC5A8 expression enhanced histones H3 and H4 acetylation in response to the histone deacetylase inhibitor, valproate, consistent with the encoded protein- SMCT1- short-chain fatty acid transport function. In addition, enhanced cell death was observed in SMCT1-expressing MLL-PTD+ AML cells treated with valproate. Within the majority of MLL-PTD AML is a mechanism in which DNA hypermethylation silences a TSG that, together with MLL-PTD, can contribute further to aberrant chromatin remodeling and altered gene expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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