TY - JOUR
T1 - DNAhypermethylation and epigenetic silencing of the tumor suppressor gene, SLC5A8, in acute myeloid leukemia with the MLL partial tandem duplication
AU - Whitman, Susan P.
AU - Hackanson, Björn
AU - Liyanarachchi, Sandya
AU - Liu, Shujun
AU - Rush, Laura J.
AU - Maharry, Kati
AU - Margeson, Dean
AU - Davulur, Ramana
AU - Wen, Jing
AU - Witte, Tatiana
AU - Yu, Li
AU - Liu, Chunhui
AU - Bloomfield, Clara D.
AU - Marcucci, Guido
AU - Plass, Christoph
AU - Caligiuri, Michael A.
PY - 2008/9/1
Y1 - 2008/9/1
N2 - 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 AfLL-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-PJD 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.
AB - 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 AfLL-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-PJD 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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U2 - 10.1182/blood-2008-01-128595
DO - 10.1182/blood-2008-01-128595
M3 - Article
C2 - 18566324
AN - SCOPUS:52649089060
SN - 0006-4971
VL - 112
SP - 2013
EP - 2016
JO - Blood
JF - Blood
IS - 5
ER -