Gene rearrangement: a novel mechanism for MDR-1 gene activation

• Published in: The Journal of clinical investigation Vol. 99; no. 8; pp. 1947 - 1957
• Main Authors: Mickley, L A, Spengler, B A, Knutsen, T A, Biedler, J L, Fojo, T
• Format: Journal Article
• Language: English
• Published: United States 15.04.1997
• Subjects: Amino Acid Sequence; Antibiotics, Antineoplastic - pharmacology; Base Sequence; Chromosomes, Human, Pair 4 - genetics; Chromosomes, Human, Pair 7 - genetics; DNA Primers - genetics; DNA, Neoplasm - genetics; Doxorubicin - pharmacology; Drug Resistance, Multiple - genetics; Gene Expression Regulation, Neoplastic; Gene Rearrangement; Genes, MDR; Humans; Hybridization, Genetic; In Situ Hybridization, Fluorescence; Molecular Sequence Data; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Neoplasm - genetics; Transcriptional Activation; Translocation, Genetic; Tumor Cells, Cultured
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI119362

Drug resistance, a major obstacle to cancer chemotherapy, can be mediated by MDR-1/P-glycoprotein. Deletion of the first 68 residues of MDR-1 in an adriamycin-selected cell line after a 4;7 translocation, t(4q;7q), resulted in a hybrid mRNA containing sequences from both MDR-1 and a novel chromosome 4 gene. Further selection resulted in amplification of a hybrid gene. Expression of the hybrid mRNA was controlled by the chromosome 4 gene, providing a model for overexpression of MDR-1. Additional hybrid mRNAs in other drug-selected cell lines and in patients with refractory leukemia, with MDR-1 juxtaposed 3' to an active gene, establishes random chromosomal rearrangements with overexpression of hybrid MDR-1 mRNAs as a mechanism of acquired drug resistance.