Methylation analysis of the human multidrug resistance 1 gene in normal and leukemic hematopoietic cells

Fryxell, KB; McGee, S. F.; Simoneaux, DK; Cl, Willman; Cornwell, MM

doi:10.1038/sj.leu.2401424

Cited by 24 publications

(11 citation statements)

References 7 publications

(7 reference statements)

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“…However, we did not find any methylation around either the Y box or GC box element. Similar results for methylation status in the promoter region have been reported in CD8-positive cells (Fryxell et al, 1999). The element Sp1 protects the promoter from de novo methylation (Brandeis et al, 1994).…”

Section: Promoter Variants and Expression Of Human Mdr1 Genesupporting

confidence: 85%

Haplotype-Oriented Genetic Analysis and Functional Assessment of Promoter Variants in theMDR1(ABCB1) Gene

Takane¹,

Kobayashi²,

Hirota³

et al. 2004

J Pharmacol Exp Ther

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Recently, a number of nucleotide variants have been described in the multidrug resistance 1 (MDR1/ABCB1) gene; however, most studies have focused on the coding region. In the present study, we identified promoter variants of the MDR1 gene and evaluated their phenotypic consequences using a reporter gene assay and the real-time polymerase chain reaction method. Ten allelic variants were detected in the promoter region (approximately 2 kilobases), seven of which were newly identified. Certain mutations occurred simultaneously, and a total of 10 haplotypes were observed. These promoter polymorphisms were found more frequently in Japanese than Caucasians. Some haplotypes were associated with changes in luciferase activity and placental and hepatic mRNA levels. We also determined DNA methylation status in the proximal promoter region of the MDR1 gene. The promoter region around potential binding sites for transcription factors was found to be hypomethylated and thus likely to be independent of the gene expression. Nucleotide and/or haplotype variants not only in the coding region but also in the promoter region of the MDR1 gene may be important for interindividual differences of P-glycoprotein expression.

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Section: Promoter Variants and Expression Of Human Mdr1 Genesupporting

confidence: 85%

Haplotype-Oriented Genetic Analysis and Functional Assessment of Promoter Variants in theMDR1(ABCB1) Gene

Takane¹,

Kobayashi²,

Hirota³

et al. 2004

J Pharmacol Exp Ther

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“…Therefore, we conclude that the transcription of the MDR1 gene is not regulated through methylation changes of the promoter region. Fryxell et al 45 suggested in their detailed study that methylation changes upstream of the promoter, in an ALU repeat may be important for transcription regulation, but they did not show a correlation between the methylation level of the ALU repeat and transcription level of the MDR1 gene. The only study that showed a correlation between MDR1 expression and methylation of the MDR1 gene was performed by Kantharidis et al 46 They examined two AML cell lines, of which only one expressed MDR1.…”

Section: Discussionmentioning

confidence: 92%

MDR1 expression in poor-risk acute myeloid leukemia with partial or complete monosomy 7

et al. 2001

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Expression of the multidrug resistance (MDR1) phenotype, encoded by the MDR1 gene, is an adverse prognostic factor for CR and survival in acute myeloid leukemia (AML). Other prognostic factors, such as specific cytogenetic abnormalities, have been identified in AML. We have investigated the expression of the MDR1 gene in untreated AML patients with monosomy 7 (n = 12), and partial deletions (n = 7) of the long arm of chromosome 7 (respectively −7/7q−), because of the extremely bad prognosis associated with these cytogenetic abnormalities and because of the fact that the MDR1 gene is located on chromosome 7q21.1.The findings were compared with the level of MDR1 expression in a group of 42 other AML patients, matched for age with favourable, neutral or complex cytogenetic abberations. MDR1 mRNA expression, as measured by the RNase protection assay was significantly higher in the −7/7q− group vs other AML patients (median 1.3 vs 0.1 arbitrary units, P = 0.02). Protein expression of MDR1 in the −7/7q− group, as determined with the monoclonal antibody MRK16, was found to be similar to the levels found in the control group. With a functional rhodamine retention assay using the modulator PSC833, increased MDR1 activity was observed in the −7/7q− group as compared to the control group of patients (P = 0.05). Considering the higher MDR1 mRNA expression and equal or slightly elevated level of protein expression of MDR1, we studied the presence of MDR1 genes in this group of −7/7q− patients. Fluorescence in situ hybridization (FISH) studies, using a specific MDR1 probe revealed no loss of an MDR1 allele in any of the deleted q− arms of the seven patients with 7q−, whereas all monosomy 7 patients lacked one MDR1 gene homologue. To determine whether there was selective loss of the MDR1 gene in the −7/7q− patients, the genetic polymorphism of the MDR1 gene was used. Both allelic variants (G and T) were represented in the −7/7q− and in the control group, showing a predominance for GT at position 2677 of the MDR1 gene in the control group. In the 12 monosomy 7 patients loss of the MDR1 allele was random. Methylation studies of the CpG island of the MDR1 gene revealed no hypermethylation in any of the −7/7q− patients. We conclude that MDR1 expression in −7/7q− AML patients is upregulated at transcriptional, but not at translational level, suggesting that mechanisms other than MDR1 are responsible for the poor prognosis in these patients. Leukemia (2001) 15, 398-405.

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“…For example, NF-IL6 binding site was shown to be more important than GCboxes in MDR-1 regulation in HTLV-1 infected cell lines. 25 Furthermore, Fryxell et al 26 described the methylation status of the CpG-rich domain as not acting as a switch regulating MDR-1 gene expression. Intracellular levels of various transcriptional factors may vary in cells, which may explain these conflicting results.…”

Section: Discussionmentioning

confidence: 99%

Decitabine (5-Aza-2′-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells

2000

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Methylation analysis of the human multidrug resistance 1 gene in normal and leukemic hematopoietic cells

Cited by 24 publications

References 7 publications

Haplotype-Oriented Genetic Analysis and Functional Assessment of Promoter Variants in theMDR1(ABCB1) Gene

Haplotype-Oriented Genetic Analysis and Functional Assessment of Promoter Variants in theMDR1(ABCB1) Gene

MDR1 expression in poor-risk acute myeloid leukemia with partial or complete monosomy 7

Decitabine (5-Aza-2′-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells

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