Bim and Bad mediated imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic

Junya Kuroda, Hamsa Puthalakath, Mark S. Cragg, Priscilla N. Kelly, Philippe Bouillet, David C S Huang, Shinya Kimura, Oliver G. Ottmann, Brian Druker, Andreas Villunger, Andrew W. Roberts, Andreas Strasser

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)14907-14912
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number40
DOIs
StatePublished - Oct 3 2006

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Puma
Drug Combinations
RNA Interference
Imatinib Mesylate
Leukemia
Pharmacology
Apoptosis
Genes
Neoplasms
Proteins
Therapeutics
ABT-737

Keywords

  • Apoptosis
  • Bcl-2
  • Cancer
  • Imatinib mesylate
  • Leukemia

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Bim and Bad mediated 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; Villunger, Andreas; Roberts, Andrew W.; Strasser, Andreas.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 40, 03.10.2006, p. 14907-14912.

Research output: Contribution to journalArticle

Kuroda, J, Puthalakath, H, Cragg, MS, Kelly, PN, Bouillet, P, Huang, DCS, Kimura, S, Ottmann, OG, Druker, B, Villunger, A, Roberts, AW & Strasser, A 2006, 'Bim and Bad mediated 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 United States of America, vol. 103, no. 40, pp. 14907-14912. https://doi.org/10.1073/pnas.0606176103
Kuroda, Junya ; Puthalakath, Hamsa ; Cragg, Mark S. ; Kelly, Priscilla N. ; Bouillet, Philippe ; Huang, David C S ; Kimura, Shinya ; Ottmann, Oliver G. ; Druker, Brian ; Villunger, Andreas ; Roberts, Andrew W. ; Strasser, Andreas. / Bim and Bad mediated imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 40. pp. 14907-14912.
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