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Genetic Polymorphism in MDR-1: A Tool for Examining
Allelic Expression in Normal Cells, Unselected and Drug-Selected
Cell Lines, and Human Tumors
Lyn A. Mickley,
Jong-Seok Lee,
Zheng Weng,
Zhirong Zhan,
Manuel Alvarez,
Wyndham Wilson,
Susan E. Bates, and
Tito Fojo
From the Medicine Branch, Division of Clinical Sciences
(DCS), National Cancer Institute (NCI), Bethesda, MD; and
the Department of Internal Medicine, Gyeongsang National University,
Chinju, Kyungnam, South Korea.
By using RNase protection analysis, residues 2677 and 2995 of
MDR-1 were identified as sites of genetic polymorphism. Through use of oligonucleotide hybridization, the genomic content and expression of individual MDR-1 alleles were examined in normal tissues, unselected and drug selected cell lines, and malignant lymphomas. In normal tissues, unselected 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 concentrations of
vincristine. The resistant sublines expressed only one allele and had a
hybrid MDR-1 gene composed of non-MDR-1 sequences
proximal to MDR-1. Previous studies showing hybrid
MDR-1 genes after rearrangements provided a potential
explanation for activation and expression of one MDR-1 allele.
We conclude that oligonucleotide hybridization can be used as a
sensitive tool to examine relative allelic expression of MDR-1,
and can identify abnormal expression from a single allele. Acquired
drug resistance in vitro and in patients is often associated with
expression of a single MDR-1 allele, and this can be a marker
of a hybrid MDR-1 gene.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1749-1756
© 1998 by The American Society of Hematology.
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