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DNA Methylation in ATRA-treated Leukemia Cell Lines Lacking a PML-RAR Chromosome Translocation.

Miftakhova, Regina LU ; Sandberg, Tove LU ; Hedblom, Andreas LU ; Nevzorova, Tatyana; Persson, Jenny L LU and Bredberg, Anders LU (2012) In Anticancer Research 32(11). p.4715-4722
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... (More)
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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Anticancer Research
volume
32
issue
11
pages
4715 - 4722
publisher
International Institute of Cancer Research
external identifiers
  • wos:000311524500011
  • pmid:23155234
  • scopus:84872670138
ISSN
1791-7530
language
English
LU publication?
yes
id
aad8ede3-1bae-4460-9bd2-7e1935364495 (old id 3218924)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23155234?dopt=Abstract
date added to LUP
2012-12-03 19:41:20
date last changed
2017-11-12 04:07:51
@article{aad8ede3-1bae-4460-9bd2-7e1935364495,
  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&lt;0.01) and U937 cells (p&lt;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.},
  author       = {Miftakhova, Regina and Sandberg, Tove and Hedblom, Andreas and Nevzorova, Tatyana and Persson, Jenny L and Bredberg, Anders},
  issn         = {1791-7530},
  language     = {eng},
  number       = {11},
  pages        = {4715--4722},
  publisher    = {International Institute of Cancer Research},
  series       = {Anticancer Research},
  title        = {DNA Methylation in ATRA-treated Leukemia Cell Lines Lacking a PML-RAR Chromosome Translocation.},
  volume       = {32},
  year         = {2012},
}