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, J; Puthalakath, H; Cragg, MS; Kelly, PN; Bouillet, P; Huang, DCS; Kimura, S; Ottmann, OG; Druker, BJ; Villunger, A; Roberts, AW; Strasser, A

Author(s): Kuroda, J; Puthalakath, H; Cragg, MS; Kelly, PN; Bouillet, P; Huang, DCS; Kimura, S; Ottmann, OG; Druker, BJ; Villunger, A; Roberts, AW; Strasser, A;
Details: Publication Year 2006-10-03,Volume 103,Issue #40,Page 14907-14912
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
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.
Publisher: NATL ACAD SCIENCES
Keywords: BH3-ONLY PROTEINS; APOPTOTIC RESPONSES; MYELOID-LEUKEMIA; BCL-2; PHOSPHORYLATION; ACTIVATION; DEATH; DEGRADATION; EXPRESSION; LYMPHOMA
Publisher's Version: https://doi.org/10.1073/pnas.0606176103
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2006-10-03 12:00:00