Abstract
The purpose of this study was to explore the characteristics and functions of BH3-only proteins Puma, Noxa and Bim in the prognosis, therapy and drug resistance of chronic lymphocytic leukemia (CLL). Puma, Noxa and Bim mRNAs were evaluated by real-time quantitative reverse transcriptase-polymerase chain reaction, and correlations between their expression levels and CLL prognostic markers were analyzed. Primary CLL samples were treated in vitro with fludarabine to investigate the role of Puma, Noxa and Bim in the response to chemotherapeutic drugs which act through activation of the p53 pathway. We found that a low expression level of Puma was associated with some markers of poor prognosis. However, the level of Noxa or Bim was not different in patients with CLL with variant clinical features and prognostic factors. Puma expression was up-regulated after fludarabine treatment in primary CLL cells, but there was no significant difference for Noxa and Bim. Up-regulation of Puma occurred only in CLL cells with functional p53. CLL cells with p53 abnormalities were deficient in the activation of Puma by chemotherapeutics. These results suggest that a lack of Puma induction may contribute to the development of resistance to anticancer agents in CLL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-ribosyl Cyclase 1 / metabolism
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Aged
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Aged, 80 and over
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Antineoplastic Agents / therapeutic use
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Apoptosis
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Bcl-2-Like Protein 11
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Cell Line, Tumor
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Female
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Gene Expression Regulation, Leukemic
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Humans
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Immunoglobulin Heavy Chains / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Middle Aged
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Mitochondrial Membrane Transport Proteins
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Mutation
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Neoplasm Staging
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Vidarabine / analogs & derivatives
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Vidarabine / therapeutic use
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ZAP-70 Protein-Tyrosine Kinase / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Immunoglobulin Heavy Chains
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Membrane Proteins
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Mitochondrial Membrane Transport Proteins
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PMAIP1 protein, human
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RTL10 protein, human
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Tumor Suppressor Protein p53
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ZAP-70 Protein-Tyrosine Kinase
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ADP-ribosyl Cyclase 1
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Vidarabine
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fludarabine