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Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype

Leukemia volume 15, pages 1823–1833 (2001)Cite this article

Abstract

A characteristic feature of chronic myeloid leukaemia (CML) is the inevitable advancement from a treatable chronic phase to a fatal, drug-resistant stage referred to as blast crisis. The molecular mechanisms responsible for this disease transition remain unknown. As increased expression of Bcr-Abl has been associated with blast crisis CML, we have established transfectants in 32D cells that express low and high levels of Bcr-Abl, and assessed their drug sensitivity. Cells with high Bcr-Abl expression levels are resistant to conventional cytotoxic drugs, and also require higher levels of STI571 (an inhibitor of Bcr-Abl), to induce cell death. Co-treatment with cytotoxic drugs and STI571 increased the sensitivity of the drug-resistant cells. Despite the drug-resistant phenotype, high Bcr-Abl levels concomitantly increased the expression of p53, p21, Bax and down-regulated Bcl-2. These cells maintain a survival advantage irrespective of a reduced proportion of cycling cells and the pro-apoptotic shift in gene expression. In addition, the level of Bcr-Abl expression (high or low) does not alter the growth factor independence and elevated Bcl-xL expression observed. Our study indicates that drug resistance can be primarily attained by increased Bcr-Abl expression, and highlights the potential of therapy which combines STI571 with conventional cytotoxic drugs.

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Acknowledgements

We thank Dr Brian Druker for the 32D cell line and Novartis for providing STI571. We thank Dr Ruaidhri Carmody for helpful discussions and advice. This work was funded by grants from the Irish Cancer Society. We are also grateful to the Children's Leukaemia Research Project, the Health Research Board, Ireland and Enterprise Ireland for financial support.

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  1. TG Cotter and SL McKenna: Joint senior authors

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  1. Department of Biochemistry, University College Cork, Ireland

    K Keeshan, TG Cotter & SL McKenna

  2. Department of Haematology, University of Wales College of Medicine, Cardiff, UK

    KI Mills

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Keeshan, K., Mills, K., Cotter, T. et al. Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype. Leukemia 15, 1823–1833 (2001). https://doi.org/10.1038/sj.leu.2402309

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