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

The expression of P-glycoprotein (P-gp), encoded by the MDR1 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 of MDR1 (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. (Blood. 2001;97:3605-3611)

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

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.