• Junya Kuroda, Hamsa Puthalakath, Mark S Cragg, Priscilla N Kelly, Philippe Bouillet, David C S Huang, Shinya Kimura, Oliver G Ottmann, Brian J Druker, Andreas Villunger, Andrew W Roberts, and Andreas Strasser.
• The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
• Proc. Natl. Acad. Sci. U.S.A. 2006 Oct 3; 103 (40): 14907-12.

AbstractCell 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.

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