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Expression of the multidrug resistance-associated protein (MRP) in acute and chronic leukemias
H Burger1, K Nooter, G J Zaman
1Department of Medical Oncology, University Hospital Rotterdam, The Netherlands.
Abstract:
We determined the expression of the multidrug resistance-associated protein (MRP), a new putative transmembrane drug transporter, in peripheral blood cells from healthy volunteers as well as from 60 patients with acute or chronic leukemia, using an RNase protection assay. MRP appeared to be ubiquitously expressed at low levels in all nonmalignant hemopoietic cell types, reflecting its basal constitutive expression. In acute myelocytic leukemia (AML) (n = 16), one of nine untreated patients and two of seven patients with prior chemotherapy showed significant hyperexpression of MRP. In chronic lymphocytic leukemia (CLL) (n = 21), either treated (n = 8) or untreated (n = 13), a high percentage (15 of 21: 71% had relatively high expression levels of the MRP gene. In contrast, low MRP expression levels were detected in acute lymphocytic leukemia (n = 14), and in chronic myelocytic leukemia (n = 9). DNA analysis by Southern blotting did not reveal amplification of the MRP gene in the leukemia samples, including those with elevated MRP mRNA levels. We conclude that relatively high expression of MRP is occasionally observed in AML and at high frequency in CLL, irrespective of treatment, probably due to transcriptional activation and/or increased mRNA stability.
Insights
Multidrug resistance-associated protein (MRP) is highly expressed in chronic lymphocytic leukemia (CLL) and occasionally in acute myeloid leukemia (AML). This suggests transcriptional activation or increased mRNA stability, not gene amplification, drives MRP levels in these cancers.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- The multidrug resistance-associated protein (MRP) is a transmembrane drug transporter.
- Understanding MRP expression is crucial for leukemia treatment.
- MRP's role in drug resistance in hematological malignancies requires further investigation.
Purpose of the Study:
- To determine the expression levels of the multidrug resistance-associated protein (MRP) in peripheral blood cells of leukemia patients.
- To compare MRP expression in various types of leukemia (AML, CLL, ALL, CML) with healthy volunteers.
- To investigate potential mechanisms, such as gene amplification, underlying altered MRP expression in leukemia.
Main Methods:
- RNase protection assay was used to quantify MRP mRNA levels in peripheral blood cells.
- Peripheral blood cells from healthy volunteers and 60 leukemia patients were analyzed.
- Southern blotting was performed to assess MRP gene amplification in leukemia samples.
Main Results:
- MRP was ubiquitously expressed at low levels in nonmalignant hematopoietic cells.
- Significant MRP hyperexpression was observed in a subset of acute myeloid leukemia (AML) patients.
- High MRP expression levels were detected in 71% of chronic lymphocytic leukemia (CLL) patients, irrespective of treatment.
- Low MRP expression was found in acute lymphocytic leukemia (ALL) and chronic myelocytic leukemia (CML).
- No MRP gene amplification was detected in any leukemia samples, even those with elevated MRP mRNA.
Conclusions:
- Elevated MRP expression occurs frequently in CLL and occasionally in AML.
- The observed high MRP expression is likely due to transcriptional activation or increased mRNA stability, not gene amplification.
- MRP's role in the pathogenesis and treatment of CLL warrants further study.