La. Mickley et al., GENETIC-POLYMORPHISM IN MDR-1 - A TOOL FOR EXAMINING ALLELIC EXPRESSION IN NORMAL-CELLS, UNSELECTED AND DRUG-SELECTED CELL-LINES, AND HUMANTUMORS, Blood, 91(5), 1998, pp. 1749-1756
By using RNase protection analysis, residues 2677 and 2995 of MDR-1 we
re identified as sites of genetic polymorphism. Through use of oligonu
cleotide hybridization, the genomic content and expression of individu
al MDR-1 alleles were examined in normal tissues, unselected and drug
selected cell lines, and malignant lymphomas, In normal tissues, unsel
ected cell lines, and untreated malignant lymphoma samples, expression
of MDR-1 from both alleles was similar. In contrast, in drug selected
cell lines, and in relapsed malignant lymphoma samples, expression of
one allele was found in a large percentage of samples. To understand
how expression of one allele occurs, two multidrug resistant sublines
were isolated by exposing a Burkitt lymphoma cell line to increasing c
oncentrations of vincristine. The resistant sublines expressed only on
e allele and had a hybrid MDR-1 gene composed of non-MDR-1 sequences p
roximal to MDR-1. Previous studies showing hybrid MDR-1 genes after re
arrangements provided a potential explanation for activation and expre
ssion of one MDR-1 allele. We conclude that oligonucleotide hybridizat
ion can be used as a sensitive tool to examine relative allelic expres
sion of MDR-1, and can identify abnormal expression from a single alle
le. Acquired drug resistance in vitro and in patients is often associa
ted with expression of a single MDR-1 allele, and this can be a marker
of a hybrid MDR-1 gene. (C) 1998 by The American Society of Hematolog
y.