Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic.
basic_science · Level V
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- Record sourced from PubMed, PMID 16997913.
- Also identified by PMC identifier 1595449.
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Abstract
Cell killing is a critical pharmacological activity of imatinib to eradicate Bcr/Abl+ leukemias. We found that imatinib kills Bcr/Abl+ leukemic cells by triggering the Bcl-2-regulated apoptotic pathway. Imatinib activated several proapoptotic BH3-only proteins: bim and bmf transcription was increased, and both Bim and Bad were activated posttranslationally. Studies using RNAi and cells from gene-targeted mice revealed that Bim plays a major role in imatinib-induced apoptosis of Bcr/Abl+ leukemic cells and that the combined loss of Bim and Bad abrogates this killing. Loss of Bmf or Puma had no effect. Resistance to imatinib caused by Bcl-2 overexpression or loss of Bim (plus Bad) could be overcome by cotreatment with the BH3 mimetic ABT-737. These results demonstrate that Bim and Bad account for most, perhaps all, imatinib-induced killing of Bcr/Abl+ leukemic cells and suggest previously undescribed drug combination strategies for cancer therapy.
Medical subject headings
- Apoptosis Regulatory Proteins
- Biphenyl Compounds
- Cytotoxicity, Immunologic
- Drug Resistance, Neoplasm
- Membrane Proteins
- Piperazines
- Protein-Tyrosine Kinases
- Proto-Oncogene Proteins
- Pyrimidines
- bcl-Associated Death Protein