Gene rearrangement: a novel mechanism for MDR-1 gene activation.

Mickley, Lyn A.; Spengler, Barbara A.; Knutsen, Turid; Biedler, June L.; Fojo, Tito

doi:10.1172/jci119362

Cited by 93 publications

(92 citation statements)

References 30 publications

(22 reference statements)

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“…In these samples, the MDR1 promoter and exon I sequences (region PCR 2), but not intron I sequences (region PCR 3), were completely methylated in one out of four subclones for patient D, and in all four subclones analyzed for patient E (Figure 3a and b). It is possible that MDR1 is activated due to a rearrangement in the MDR1 locus in some AML patient 46 have demonstrated that increased MDR1 expression can occur by MDR1 gene rearrangements in acute lymphoblastic leukemia (ALL) samples as well as hematopoietic cell lines. A subsequent study provided evidence of allele switching (predominant MDR1 gene expression from a single allele) during the development of acquired drug resistance in leukemias.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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Expression of the human multidrug resistance 1 gene (MDR1), which encodes the P-glycoprotein transmembrane efflux pump, has been associated with treatment failure of some leukemias, primarily acute myeloid leukemia (AML). To elucidate the epigenetic events associated with overexpression of MDR1 in AML, we analyzed the methylation status of a 2000 bp region within the MDR1 locus using a bisulphite genomic sequencing technique. A CpG-rich domain, approximately 1 kb in size, encompasses the promoter region, exon I, and intron I. This domain was found to be relatively unmethylated in five out of six primary and cultured human hematopoietic cells, as well as five out of six AML patient samples, independent of the MDR1 phenotype. The data suggest that the methylation status of the CpG-rich domain does not act as a 'switch' to regulate expression of the MDR1 gene. In addition, we found an upstream Alu repeat sequence to be unmethylated in three out of five cultured hematopoietic cell lines, both MDR1 expressing and non-expressing. However, analysis of primary CD8-positive T cells and AML patient samples revealed dense methylation of this region which is consistent with methylation of Alu repeat sequences observed in somatic tissues.

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Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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“…The presence and allelic expression of the genetic polymorphism of MDR1 at position 2677 was detected using oligonu-cleotide hybridization as described by Mickley et al 36,37 The PCR products were dot-blotted to a Zeta Probe blotting membrane (Bio-Rad, Hercules, CA, USA) which was prehybridized for 30 min at 50°C in 5 × SSPE, 0.5% SDS, 5 × Denhardt's, 50 g/ml denatured herring sperm DNA. Hybridization, using radiolabeled oligonucleotides as allele-specific probes, was performed for 2 h at 50°C after which the blots were rinsed twice at room temperature in 2 × SSPE, 0.1% SDS and subsequently washed for 10 min at 55°C in 5 × SSPE, 0.1% SDS.…”

Section: Detection Of Mdr1 Polymorphism and Allelic Expressionmentioning

confidence: 99%

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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“…MCF-7 TH was selected by continuous exposure to 1 Ag/mL Adriamycin. The cell lines are summarized in Table 1, with appropriate references (12)(13)(14)(15)(16).…”

Section: Methodsmentioning

confidence: 99%

“…The 5V rapid amplification of cDNA ends (RACE) kit (Invitrogen) was used to isolate the AMTs using the MDR-1 gene-specific primers GSP1 and GSP2 as reported previously (12).…”

Section: Methodsmentioning

confidence: 99%

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Aberrant Transcription from an Unrelated Promoter Can Result in MDR-1 Expression following Drug Selection In vitro and in Relapsed Lymphoma Samples

et al. 2005

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Gene rearrangement: a novel mechanism for MDR-1 gene activation.

Cited by 93 publications

References 30 publications

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

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

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

Aberrant Transcription from an Unrelated Promoter Can Result in MDR-1 Expression following Drug Selection In vitro and in Relapsed Lymphoma Samples

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