Gene rearrangement: A novel mechanism for MDR-1 gene activation Journal Article


Authors: Mickley, L. A.; Spengler, B. A.; Knutsen, T. A.; Biedler, J. L.; Fojo, T.
Article Title: Gene rearrangement: A novel mechanism for MDR-1 gene activation
Abstract: 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.
Keywords: cancer chemotherapy; human tissue; gene deletion; mutation; doxorubicin; polymerase chain reaction; neoplasms; in situ hybridization, fluorescence; drug resistance; tumor cells, cultured; gene activation; gene expression regulation, neoplastic; gene rearrangement; amino acid sequence; molecular sequence data; rna, messenger; dna, neoplasm; chromosome rearrangement; base sequence; translocation, genetic; dna primers; colon carcinoma; antibiotics, antineoplastic; rna, neoplasm; p-glycoprotein; drug resistance, multiple; chromosome 4; chromosomes, human, pair 4; chromosomes, human, pair 7; genes, mdr; gene rearrangements; humans; human; priority journal; article; mdr-1; hybridization, genetic
Journal Title: Journal of Clinical Investigation
Volume: 99
Issue: 8
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 1997-04-15
Start Page: 1947
End Page: 1957
Language: English
PUBMED: 9109439
PROVIDER: scopus
PMCID: PMC508019
DOI: 10.1172/JCI119362
DOI/URL:
Notes: Article -- Export Date: 17 March 2017 -- Source: Scopus
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MSK Authors
  1. June   Biedler
    25 Biedler