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 J. Druker, Andreas Villunger, Andrew W. Roberts, Andreas Strasser

Research output: Contribution to journalArticlepeer-review

281 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • General

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