Gene Rearrangement: A Novel Mechanism for MDR-1 Gene Activation

J Clin Invest. 1997 Apr 15;99(8):1947-57. doi: 10.1172/JCI119362.

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.

MeSH terms

  • 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

Substances

  • Antibiotics, Antineoplastic
  • DNA Primers
  • DNA, Neoplasm
  • RNA, Messenger
  • RNA, Neoplasm
  • Doxorubicin