Bim and Bad Mediate Imatinib-Induced Killing of Bcr/Abl⁺ Leukemic Cells, and Resistance Due to Their Loss Is Overcome by a BH3 Mimetic

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-10, Vol.103 (40), p.14907-14912
• Main Authors: Kuroda, Junya, Puthalakath, Hamsa, Cragg, Mark S., Kelly, Priscilla N., Bouillet, Philippe, Huang, David C. S., Kimura, Shinya, Ottmann, Oliver G., Druker, Brian J., Villunger, Andreas, Roberts, Andrew W., Strasser, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; bcl-Associated Death Protein - metabolism; Benzamides; Biological Sciences; Biphenyl Compounds - pharmacology; Cell growth; Cell Line, Tumor; Cell lines; Cell Transformation, Neoplastic; Chronic myeloid leukemia; Cytotoxicity, Immunologic - drug effects; Drug Resistance, Neoplasm; Drug therapy; Fetus - cytology; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; K562 cells; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Liver - cytology; Liver cells; Medical research; Membrane Proteins - genetics; Membrane Proteins - metabolism; Messenger RNA; Mice; Myeloid Progenitor Cells - cytology; Nitrophenols; Pharmacology; Piperazines - pharmacology; Progenitor cells; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrimidines - pharmacology; Rodents; Sulfonamides
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0606176103

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, imatinibinduced killing of Bcr/Abl⁺ leukemic cells and suggest previously undescribed drug combination strategies for cancer therapy.