Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic
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. and Strasser, Andreas (2006) Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proceedings of the National Academy of Sciences of the USA, 103, (40), 14907-14912. (doi:10.1073/pnas.0606176103).
Download
Full text not available from this repository.
Description/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.
| Item Type: | Article |
|---|---|
| ISSNs: | 0027-8424 (print) |
| Related URLs: | |
| Keywords: | apoptosis, imatinib mesylate, Bcl-2, cancer, leukemia |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) Q Science > QH Natural history > QH426 Genetics |
| Divisions: | University Structure - Pre August 2011 > School of Medicine > Cancer Sciences |
| Item ID: | 44622 |
| Date Deposited: | 01 Mar 2007 |
| Last Modified: | 02 Mar 2012 11:29 |
| Contributors: | Kuroda, Junya (Author) Puthalakath, Hamsa (Author) Cragg, Mark S. (Author) Kelly, Priscilla N. (Author) Bouillet, Philippe (Author) Huang, David C.S. (Author) Kimura, Shinya (Author) Ottmann, Oliver G. (Author) Druker, Brian J. (Author) Villunger, Andreas (Author) Roberts, Andrew W. (Author) Strasser, Andreas (Author) |
| Date: | 2006 |
| Status: | Published |
| URI: | http://eprints.soton.ac.uk/id/eprint/44622 |
Actions (login required)
 |
View Item |
