Peer-Reviewed Journal Details
Mandatory Fields
Keeshan, K,Mills, KI,Cotter, TG,McKenna, SL;
2001
January
Official Journal of The Leukemia Society of America
Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype
Validated
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Optional Fields
Bcr-Abl levels CML drug resistance STl571 CHRONIC MYELOGENOUS LEUKEMIA CHRONIC MYELOID-LEUKEMIA TYROSINE KINASE INHIBITOR CHRONIC MYELOCYTIC-LEUKEMIA COLONY-STIMULATING FACTOR HEMATOPOIETIC-CELLS POSITIVE CELLS BLASTIC TRANSFORMATION INTERFERON-ALPHA MESSENGER-RNA
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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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