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

L A Mickley1, B A Spengler, T A Knutsen

  • 1Medicine Branch, DCS, NCI, Bethesda, Maryland 20892, USA.

The Journal of Clinical Investigation
|April 15, 1997
PubMed

Insights

Acquired drug resistance in cancer can arise from hybrid messenger RNAs (mRNAs) involving the MDR-1 gene. Chromosomal rearrangements can lead to overexpression of these hybrid mRNAs, contributing to multidrug resistance.

Area of Science:

  • Molecular biology
  • Cancer research
  • Genetics

Background:

  • Multidrug resistance (MDR) is a significant challenge in cancer chemotherapy.
  • The MDR-1 gene, encoding P-glycoprotein, is a key mediator of drug resistance.

Purpose of the Study:

  • To investigate the role of chromosomal rearrangements in MDR-1 expression and acquired drug resistance.
  • To elucidate the mechanism of hybrid mRNA formation and its impact on P-glycoprotein levels.

Main Methods:

  • Analysis of adriamycin-selected cell lines with chromosomal translocations.
  • Identification and characterization of hybrid mRNA transcripts.
  • Gene amplification studies.
  • Expression analysis of hybrid MDR-1 mRNAs.

Main Results:

  • A 4;7 translocation in drug-selected cells created a hybrid mRNA from MDR-1 and a novel chromosome 4 gene.
  • Further selection led to amplification of this hybrid gene.
  • Expression of the hybrid mRNA was regulated by the chromosome 4 gene, modeling MDR-1 overexpression.
  • Similar hybrid mRNAs were found in other drug-selected cell lines and leukemia patients.

Conclusions:

  • Random chromosomal rearrangements juxtaposing MDR-1 3' to active genes can generate hybrid mRNAs.
  • Overexpression of these hybrid MDR-1 mRNAs is a mechanism for acquired multidrug resistance in cancer.
  • This provides a model for understanding drug resistance in refractory leukemia.

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