Hypomethylation Status of CpG Sites at the Promoter Region and Overexpression of the Human MDR1 Gene in Acute Myeloid Leukemias

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4296-4307 ◽  
Author(s):  
Masaharu Nakayama ◽  
Morimasa Wada ◽  
Taishi Harada ◽  
Jun Nagayama ◽  
Hitoshi Kusaba ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Promoter Region ◽  
Methylation Status ◽  
Inverse Correlation ◽  
Mdr1 Gene ◽  
Clinical Samples ◽  
Necessary Condition ◽  
Cpg Sites ◽  
P Glycoprotein ◽  
Acute Myeloid

Selection of human cells for resistance to vincristine or doxorubicin often induces overexpression of the multidrug resistance 1 gene (MDR1), which encodes the cell surface P-glycoprotein, as a result of gene amplification or transcriptional activation. Moreover, overexpression of the MDR1 gene has been shown to be associated closely with clinical outcome in various hematological malignancies, including acute myeloid leukemia (AML). However, the precise mechanism underlying overexpression of the MDR1 gene during acquisition of drug resistance remains unclear. We recently described an inverse correlation between the methylation status of CpG sites at the promoter region and expression of the MDR1 gene in malignant cell lines. In this study, we expanded this analysis to 42 clinical AML samples. We adapted a quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay for gene expression and a quantitative PCR after digestion by Hpa II for methylation status of the MDR1gene. We observed a statistically significant inverse correlation between methylation and MDR1 expression in clinical samples. The hypomethylation status of the MDR1 promoter region might be a necessary condition for MDR1 gene overexpression and establishment of P-glycoprotein–mediated multidrug resistance in AML patients.

Hypomethylation Status of CpG Sites at the Promoter Region and Overexpression of the Human MDR1 Gene in Acute Myeloid Leukemias

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4296-4307 ◽  
Author(s):  
Masaharu Nakayama ◽  
Morimasa Wada ◽  
Taishi Harada ◽  
Jun Nagayama ◽  
Hitoshi Kusaba ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Promoter Region ◽  
Methylation Status ◽  
Inverse Correlation ◽  
Mdr1 Gene ◽  
Clinical Samples ◽  
Necessary Condition ◽  
Cpg Sites ◽  
P Glycoprotein ◽  
Acute Myeloid

Abstract Selection of human cells for resistance to vincristine or doxorubicin often induces overexpression of the multidrug resistance 1 gene (MDR1), which encodes the cell surface P-glycoprotein, as a result of gene amplification or transcriptional activation. Moreover, overexpression of the MDR1 gene has been shown to be associated closely with clinical outcome in various hematological malignancies, including acute myeloid leukemia (AML). However, the precise mechanism underlying overexpression of the MDR1 gene during acquisition of drug resistance remains unclear. We recently described an inverse correlation between the methylation status of CpG sites at the promoter region and expression of the MDR1 gene in malignant cell lines. In this study, we expanded this analysis to 42 clinical AML samples. We adapted a quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay for gene expression and a quantitative PCR after digestion by Hpa II for methylation status of the MDR1gene. We observed a statistically significant inverse correlation between methylation and MDR1 expression in clinical samples. The hypomethylation status of the MDR1 promoter region might be a necessary condition for MDR1 gene overexpression and establishment of P-glycoprotein–mediated multidrug resistance in AML patients.

An anti-apoptotic pattern correlates with multidrug resistance in acute myeloid leukemia patients: a comparative study of active caspase-3, cleaved PARPs, Bcl-2, Survivin and MDR1 gene

Hematology ◽  
2010 ◽  
Vol 15 (3) ◽  
pp. 135-143 ◽  
Author(s):  
Margarita L. Guenova ◽  
Gueorgui N. Balatzenko ◽  
Vessela R. Nikolova ◽  
Branimir V. Spassov ◽  
Spiro M. Konstantinov
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Comparative Study ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Mdr1 Gene ◽  
Acute Myeloid ◽  
Active Caspase

scholarly journals MDR1 gene–related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3605-3611 ◽  
Author(s):  
Marry M. van den Heuvel-Eibrink ◽  
Erik A. C. Wiemer ◽  
Marjan J. de Boevere ◽  
Bronno van der Holt ◽  
Paula J. M. Vossebeld ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Genetic Polymorphism ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clonal Selection ◽  
Survival Rates ◽  
Mdr1 Gene ◽  
Allelic Variants ◽  
P Glycoprotein ◽  
Acute Myeloid

The expression of P-glycoprotein (P-gp), encoded by theMDR1 gene, is an independent adverse prognostic factor for response and survival in de novo acute myeloid leukemia (AML). Little is known about MDR1 expression during the development of disease. The present study investigated whether MDR1 gene– related clonal selection occurs in the development from diagnosis to relapsed AML, using a genetic polymorphism of the MDR1 gene at position 2677. Expression and function of P-gp were studied using monoclonal antibodies MRK16 and UIC2 and the Rhodamine 123 retention assay with or without PSC 833. No difference was found in the levels of P-gp function and expression between diagnosis and relapse in purified paired blast samples from 30 patients with AML. Thirteen patients were homozygous for the genetic polymorphism ofMDR1 (n = 7 for guanine, n = 6 for thymidine), whereas 17 patients were heterozygous (GT). In the heterozygous patients, no selective loss of one allele was observed at relapse. Homozygosity for the MDR1 gene (GG or TT) was associated with shorter relapse-free intervals (P = .002) and poor survival rates (P = .02), compared with heterozygous patients. No difference was found in P-gp expression or function in patients with AML with either of the allelic variants of the MDR1 gene. It was concluded that P-gp function or expression is not upregulated at relapse/refractory disease and expression of one of the allelic variants is not associated with altered P-gp expression or function in AML, consistent with the fact that MDR1 gene–related clonal selection does not occur when AML evolves to recurrent disease.

scholarly journals Hypomethylation of the LH/Choriogonadotropin Receptor Promoter Region Is a Potential Mechanism Underlying Susceptibility to Polycystic Ovary Syndrome

Endocrinology ◽  
2014 ◽  
Vol 155 (4) ◽  
pp. 1445-1452 ◽  
Author(s):  
Peng Wang ◽  
Han Zhao ◽  
Tao Li ◽  
Wei Zhang ◽  
Keliang Wu ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Promoter Region ◽  
Genome Wide Association Study ◽  
Polycystic Ovary ◽  
Methylation Status ◽  
Susceptibility Gene ◽  
Potential Mechanism ◽  
Ovary Syndrome ◽  
Cpg Sites ◽  
Flanking Regions

Our previous genome-wide association study identified LH/choriogonadotropin receptor (LHCGR) as a susceptibility gene for polycystic ovary syndrome (PCOS). The objective of this study was to determine whether the genetic or epigenetic components associated with LHCGR participate in the pathogenesis of PCOS. The exons and flanking regions of LHCGR were sequenced from 192 women with PCOS, and no novel somatic mutations were identified. In addition, the methylation statuses of 6 cytosine-phosphate-guanine (CpG) sites in the promoter region of LHCGR were measured by pyrosequencing using peripheral blood cells from 85 women with PCOS and 88 control women. We identified 2 hypomethylated sites, CpG −174 (corrected P = .018) and −111 (corrected P = .006). Bisulfite sequencing then was performed to replicate these findings and detect additional CpG sites in the promoter. CpG +17 was significantly hypomethylated in women with PCOS (corrected P = .02). Methylation statuses were further evaluated using granulosa cells (GCs), and the region described was hypomethylated as a whole (P = .004) with 8 significantly hypomethylated sites (CpG −174, −148, −61, −43, −8, +10, +17, and +20). Transcription of LHCGR was elevated in women with PCOS compared with that in control women (P < .01). These findings were consistent with the decreased LHCGR methylation status associated with PCOS. The tendency of LHCGR to be hypomethylated across different tissues and its corresponding expression level suggest that hypomethylation of LHCGR is a potential mechanism underlying susceptibility to PCOS. Further studies are needed to evaluate whether a causal relationship exists between LHCGR methylation status and PCOS.

scholarly journals Methylation status of CpG sites in the promoter region of the OY-TES-1 gene in hepatoma cell lines

2011 ◽  
Vol 19 (21) ◽  
pp. 2274
Author(s):  
Wei-Wei Wang ◽  
Rong Fan ◽  
Bin Luo ◽  
Wen-Wen Guo ◽  
Qing-Mei Zhang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Promoter Region ◽  
Hepatoma Cell ◽  
Methylation Status ◽  
Hepatoma Cell Lines ◽  
Cpg Sites

scholarly journals Tetrandrine Interaction with ABCB1 Reverses Multidrug Resistance in Cancer Cells Through Competition with Anti-Cancer Drugs Followed by Downregulation of ABCB1 Expression

Molecules ◽  
2019 ◽  
Vol 24 (23) ◽  
pp. 4383 ◽  
Author(s):  
Dan Liao ◽  
Wei Zhang ◽  
Pranav Gupta ◽  
Zi-Ning Lei ◽  
Jing-Quan Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Cellular Localization ◽  
Treatment Time ◽  
Mrna Level ◽  
Chemotherapeutic Agents ◽  
Mdr1 Gene ◽  
P Glycoprotein ◽  
Abcb1 Transporter

The overexpression of ABC transporters induced by anticancer drugs has been found to be the main cause of multidrug resistance. It is actually also a strategy by which cancer cells escape being killed. Tetrandrine is a natural product extracted from the stem of Tinospora crispa. In this study, tetrandrine showed synergistic cytotoxic activity in combinational use with chemotherapeutic drugs, such as Doxorubicin, Vincristine, and Paclitaxel, in both drug-induced and MDR1 gene-transfected cancer cells that over-expressed ABCB1/P-glycoprotein. Tetrandrine stimulated P-glycoprotein ATPase activity, decreased the efflux of [3H]-Paclitaxel and increased the intracellular accumulation of [3H]-Paclitaxel in KB-C2 cells. Furthermore, SW620/Ad300 and KB-C2 cells pretreated with 1 μM tetrandrine for 72 h decreased P-glycoprotein expression without changing its cellular localization. This was demonstrated through Western blotting and immunofluorescence analysis. Interestingly, down-regulation of P-glycoprotein expression was not correlated with gene transcription, as the MDR1 mRNA level exhibited a slight fluctuation in SW620/Ad300 and KB-C2 cells at 0, 24, 48, and 72 h treatment time points. In addition, molecular docking analysis predicted that tetrandrine had inhibitory potential with the ABCB1 transporter. Our results suggested that tetrandrine can antagonize MDR in both drug-selected and MDR1 gene-transfected cancer cells by down regulating the expression of the ABCB1 transporter, followed by increasing the intracellular concentration of chemotherapeutic agents. The combinational therapy using tetrandrine and other anticancer drugs could promote the treatment efficiency of drugs that are substrates of ABCB1.

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