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Low incidence of MDR1 expression in acute promyelocytic leukaemia
1Department of Hematology, University of Texas M.D. Anderson Cancer Center, Houston, USA.
Abstract:
The MDR1 gene product, P-glycoprotein, functions as a transmembrane efflux pump for certain cytotoxic agents including anthracyclines. Based upon the clinical observation that patients with acute promyelocytic leukaemia (APL) respond favourably to anthracyclines, we hypothesized that APL cells may have low levels of MDR1 expression. We therefore investigated MDR1 expression in 10 patients with APL and compared results with those obtained in 18 patients with other subtypes of acute myelogenous leukaemia (AML). Prior to reverse transcriptase polymerase chain reaction with MDR1 specific primers, leukaemic cells were purified by fluorescence activated cell sorting to exclude normal haemopoietic cells, in particular lymphocytes, from the MDR1 analysis. In sorted APL cells, MDR1 expression was detected in only two of 10 patients, which was significantly different from findings in other AML subtypes (MDR1 expression in 14/18 patients; P < 0.01). When unsorted specimens from APL patients were studied, five of six cases were MDR1 positive, whereas sorted APL cells were shown to express MDR1 mRNA in only one of these cases. MDR1 mRNA levels expressed as MDR1/beta-2 microglobulin ratios were significantly lower in APL (0.24 +/- 0.2, mean +/- SD) than in AML (0.75 +/- 0.48; P < 0.01). We conclude that low or absent expression of MDR1 in APL cells may contribute to the efficacy of anthracyclines in the treatment of APL.
Insights
Acute promyelocytic leukaemia (APL) cells show significantly lower MDR1 gene expression compared to other acute myelogenous leukaemia (AML) subtypes. This reduced MDR1 expression may explain the effectiveness of anthracycline chemotherapy in treating APL.
Area of Science:
- Molecular Biology
- Oncology
- Haematology
Background:
- The MDR1 gene encodes P-glycoprotein, a transmembrane efflux pump.
- P-glycoprotein actively transports cytotoxic agents, including anthracyclines, out of cells.
- Clinical observations suggest favorable responses of acute promyelocytic leukaemia (APL) to anthracyclines.
Purpose of the Study:
- To investigate MDR1 gene expression levels in APL cells.
- To compare MDR1 expression in APL with other subtypes of acute myelogenous leukaemia (AML).
- To determine if MDR1 expression correlates with anthracycline efficacy in APL.
Main Methods:
- Purification of leukaemic cells using fluorescence-activated cell sorting (FACS).
- Analysis of MDR1 gene expression via reverse transcriptase polymerase chain reaction (RT-PCR).
- Quantification of MDR1 mRNA levels relative to beta-2 microglobulin.
Main Results:
- MDR1 expression was detected in only 2/10 sorted APL cells, significantly lower than in 14/18 other AML subtypes (P < 0.01).
- MDR1 mRNA levels (MDR1/beta-2 microglobulin ratio) were significantly lower in APL (0.24 ± 0.2) than in AML (0.75 ± 0.48; P < 0.01).
- Analysis of unsorted APL specimens showed higher MDR1 positivity (5/6) compared to sorted cells (1/6), highlighting the importance of cell purification.
Conclusions:
- APL cells exhibit significantly lower MDR1 expression compared to other AML subtypes.
- Reduced MDR1 expression in APL cells may contribute to their sensitivity to anthracycline chemotherapy.
- These findings provide a molecular basis for the clinical efficacy of anthracyclines in APL treatment.