Document Detail


Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype.
MedLine Citation:
PMID:  11753601     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
K Keeshan; K I Mills; T G Cotter; S L McKenna
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Leukemia     Volume:  15     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  2001 Dec 
Date Detail:
Created Date:  2001-12-25     Completed Date:  2002-01-22     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1823-33     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, University College Cork, Ireland.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Apoptosis / drug effects,  physiology
Cell Cycle / drug effects
Cell Division / drug effects
Cells, Cultured
Drug Resistance, Neoplasm* / genetics
Enzyme Inhibitors / pharmacology
Fusion Proteins, bcr-abl / biosynthesis*,  metabolism
Hematopoietic Stem Cells / cytology,  drug effects*,  enzymology
Humans
Interleukin-3 / pharmacology
Phenotype
Piperazines / pharmacology
Protein-Tyrosine Kinases / antagonists & inhibitors,  pharmacology
Pyrimidines / pharmacology
Transfection
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Fusion Proteins, bcr-abl; 0/Interleukin-3; 0/Piperazines; 0/Pyrimidines; BKJ8M8G5HI/imatinib; EC 2.7.10.1/Protein-Tyrosine Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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