DNA Methylation in ATRA-treated leukemia cell lines lacking a PML-RAR chromosome translocation

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DNA Methylation in ATRA-treated leukemia cell lines lacking a PML-RAR chromosome translocation

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Publication Article, peer reviewed scientific
Title DNA Methylation in ATRA-treated leukemia cell lines lacking a PML-RAR chromosome translocation
Author(s) Miftakhova, Regina ; Sandberg, Tove ; Hedblom, Andreas ; Nevzorova, Tatyana ; Persson, Jenny L. ; Bredberg, Anders
Date 2012
English abstract
Abstract A deficient retinoic acid signaling has been suggested to be an important cause of the clinical inefficacy of all-trans retinoic acid (ATRA) therapy in non-promyelocytic (non-PML) forms of acute myeloid leukemia (AML). The general aim of the present work was to explore novel ways to take advantage of the anti-leukemic potential of ATRA, and, specifically, to search for a synergism between ATRA and epigenetic drugs. Because previous reports have found no major influence of ATRA on DNA methylation, we investigated whether ATRA-mediated differentiation of the U937 and HL-60 AML cell lines, both lacking a PML-retinoic acid receptor (RAR) fusion product, is accompanied by early-appearing and weak changes in CpG methylation. We report that in HL-60 cells, by using a highly quantitative analysis of a set of genes found to be abnormally expressed in AML, polymerase chain reaction (PCR)-amplified p16 gene promoter molecules (each with 15 CpG sites), exhibited a CpG methylation level of 0-4% in untreated cells, which increased to 4-21% after treatment with ATRA for seven days. In contrast to HL-60 cells, U937 cells exhibited a very high CpG methylation level in p16, and ATRA did not influence the promoter methylation of this gene. In the total CCGG sites of the genome, analysed using a methylation-sensitive restriction enzyme, CpG methylation was significantly lower in ATRA-treated HL-60 (p<0.01) and U937 cells (p<0.05) than in controls. Taken together, our findings show that ATRA can influence DNA methylation, and suggest that future research should investigate whether epigenetic modulation may evoke a clinical effect of ATRA in leukemia.
Link http://ar.iiarjournals.org/content/32/11/4715.long (external link to publication)
Publisher International Institute of Anticancer Research
Host/Issue Anticancer Research;11
Volume 32
ISSN 1791-7530
Pages 4715-4722
Language eng (iso)
Subject(s) ATRA
DNA methylation
p16
Medicine
Research Subject Categories::MEDICINE
Handle http://hdl.handle.net/2043/14790 (link to this page)

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