Bim and Bad Mediate Imatinib-induced Killing of Bcr/Abl+ Leukemic Cells, and Resistance Due to Their Loss is Overcome by a BH3 Mimetic

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Sep 26

PMID 16997913

Citations 153

Authors

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

Affiliations

Soon will be listed here.

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.

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