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

Expression of the multidrug resistance (MDR1) phenotype, encoded by the MDR 1 gene, is an adverse prognostic factor for CR and survival in acute myeloi d leukemia (AML), Other prognostic factors, such as specific cytogenetic ab normalities, have been identified in AML, We have investigated the expressi on 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 cytogen etic 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 expre ssion in a group of 42 other AML patients, matched for age with favourable, neutral or complex cytogenetic abberations, MDR1 mRNA expression, as measu red by the RNase protection assay was significantly higher in the -7/7q- gr oup vs other AML patients (median 1.3 vs 0.1 arbitrary units, P= 0.02). Pro tein expression of MDR1 in the -7/7q-group, as determined with the monoclon al antibody MRK16, was found to be similar to the levels found in the contr ol group. With a functional rhodamine retention assay using the modulator P SC833, 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 m RNA expression and equal or slightly elevated level of protein expression o f MDR1, we studied the presence of MDR1 genes in this group of -7/7q-patien ts. Fluorescence in situ hybridization (FISH) studies, using a specific MDR 1 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 MD R1 gene homologue, To determine whether there was selective loss of the MDR 1 gene in the -7/7q- patients, the genetic polymorphism of the MDR1 gene wa s 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 g ene revealed no hypermethylation in any of the -7/7q-patients. We conclude that MDR1 expression in -7/7q- AML patients is upregulated at transcription al, but not at translational level, suggesting that mechanisms other than M DR1 are responsible for the poor prognosis In these patients.