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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.

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NEOPLASIA

Brief Report

DNA hypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication

Susan P. Whitman1,2, Björn Hackanson3, Sandya Liyanarachchi3, Shujun Liu1,2, Laura J. Rush1,4, Kati Maharry1,5, Dean Margeson1,5, Ramana Davuluri3, Jing Wen1, Tatiana Witte1, Li Yu3, Chunhui Liu3, Clara D. Bloomfield1,2, Guido Marcucci1,2, Christoph Plass3, and Michael A. Caligiuri13

1 Comprehensive Cancer Center, 2 Division of Hematology-Oncology, Department of Medicine, 3 Department of Molecular Virology, Immunology, and Medical Genetics, and 4 Department of Veterinary Biosciences, The Ohio State University, Columbus; and 5 Cancer and Leukemia Group B Statistical Center, Duke University, Durham, NC

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 mixed lineage leukemia 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.


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