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

Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic
Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic
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.
apoptosis, imatinib mesylate, Bcl-2, cancer, leukemia
0027-8424
14907-14912
Kuroda, Junya
060456d1-af67-4f6c-8b31-2477b0e201aa
Puthalakath, Hamsa
eb3724dc-846d-4a14-8925-f79a4bf6bc0e
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Kelly, Priscilla N.
c49d87b2-1d38-47f6-8c73-619ffaa49159
Bouillet, Philippe
33a3a62f-6a7b-4c61-ab93-b03832bdc9b1
Huang, David C.S.
244aec72-d007-4e85-84c2-f28eb999aa83
Kimura, Shinya
fe10681e-fce3-42aa-8698-0c465650b33c
Ottmann, Oliver G.
2987ee25-2ef7-4fe9-a1f9-cfe867ec4d26
Druker, Brian J.
6c50067e-dc21-4179-ad67-22fd8850e088
Villunger, Andreas
38b7ab19-bb1c-444e-8107-da520d3d5638
Roberts, Andrew W.
9e297ce6-5cd6-4f71-b2c8-4702fe1bf6c1
Strasser, Andreas
c9774edf-fa89-481c-8cc4-21f403859700
Kuroda, Junya
060456d1-af67-4f6c-8b31-2477b0e201aa
Puthalakath, Hamsa
eb3724dc-846d-4a14-8925-f79a4bf6bc0e
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Kelly, Priscilla N.
c49d87b2-1d38-47f6-8c73-619ffaa49159
Bouillet, Philippe
33a3a62f-6a7b-4c61-ab93-b03832bdc9b1
Huang, David C.S.
244aec72-d007-4e85-84c2-f28eb999aa83
Kimura, Shinya
fe10681e-fce3-42aa-8698-0c465650b33c
Ottmann, Oliver G.
2987ee25-2ef7-4fe9-a1f9-cfe867ec4d26
Druker, Brian J.
6c50067e-dc21-4179-ad67-22fd8850e088
Villunger, Andreas
38b7ab19-bb1c-444e-8107-da520d3d5638
Roberts, Andrew W.
9e297ce6-5cd6-4f71-b2c8-4702fe1bf6c1
Strasser, Andreas
c9774edf-fa89-481c-8cc4-21f403859700

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, 103 (40), 14907-14912. (doi:10.1073/pnas.0606176103).

Record type: 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.

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More information

Published date: 2006
Keywords: apoptosis, imatinib mesylate, Bcl-2, cancer, leukemia
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 44622
URI: http://eprints.soton.ac.uk/id/eprint/44622
ISSN: 0027-8424
PURE UUID: 34a60dde-c9dc-412f-9675-7386bebd038f
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 01 Mar 2007
Last modified: 17 Dec 2019 01:56

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Contributors

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

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