Gene rearrangement: a novel mechanism for MDR-1 gene activation.
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.
Mickley
L A
LA
Medicine Branch, DCS, NCI, Bethesda, Maryland 20892, USA.
Spengler
B A
BA
Knutsen
T A
TA
Biedler
J L
JL
Fojo
T
T
D000595:Amino Acid Sequence; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001483:Base Sequence; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D019450:Genes, MDR; D006801:Humans; D006824:Hybridization, Genetic; D017404:In Situ Hybridization, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015533:Transcriptional Activation; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D017931:DNA Primers; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D004317:Doxorubicin