Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim
Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim
DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In E?-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in E?-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of E?-Myc/Puma?/?Noxa?/? lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa?/?Puma?/?Bim?/? mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.
5256-67
Happo, Lina
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Cragg, Mark.S.
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Phipson, Belinda
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Haga, Jon M.
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Jansen, Elisa S.
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Herold, Marco J.
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Dewson, Grant
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Michalak, Ewa M.
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Vandenberg, Cassandra J.
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Smyth, Gordon K.
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Strasser, Andreas
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Cory, Suzanne
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Scott, Clare L.
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9 December 2010
Happo, Lina
5181184a-1663-431c-b212-ca2ae51e5647
Cragg, Mark.S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Phipson, Belinda
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Haga, Jon M.
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Jansen, Elisa S.
62539592-d6db-4a70-8c33-dcd2e00da8f2
Herold, Marco J.
9fd7f94c-774b-4f3f-861e-8a380c5256eb
Dewson, Grant
01c6455d-de63-43d2-b629-5a693c1d16b2
Michalak, Ewa M.
efd1edfc-9d7f-4f0b-9545-f72582f96b56
Vandenberg, Cassandra J.
b9d021bf-dc30-499d-9a1a-3c9e8b8108e9
Smyth, Gordon K.
cdf322c9-2f00-4148-b5cd-e5a371c2396b
Strasser, Andreas
c9774edf-fa89-481c-8cc4-21f403859700
Cory, Suzanne
06956155-9c3d-40b6-bf20-78b565e9c4c4
Scott, Clare L.
9aee7a06-6161-4d3b-8721-c395654dca5f
Happo, Lina, Cragg, Mark.S., Phipson, Belinda, Haga, Jon M., Jansen, Elisa S., Herold, Marco J., Dewson, Grant, Michalak, Ewa M., Vandenberg, Cassandra J., Smyth, Gordon K., Strasser, Andreas, Cory, Suzanne and Scott, Clare L.
(2010)
Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim.
Blood, 116 (24), .
(doi:10.1182/blood-2010-04-280818).
(PMID:20829369)
Abstract
DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In E?-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in E?-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of E?-Myc/Puma?/?Noxa?/? lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa?/?Puma?/?Bim?/? mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.
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e-pub ahead of print date: 9 September 2010
Published date: 9 December 2010
Organisations:
Cancer Sciences
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Local EPrints ID: 339282
URI: http://eprints.soton.ac.uk/id/eprint/339282
ISSN: 0006-4971
PURE UUID: cd96024f-313d-418b-9e69-d47cdc719ae9
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Date deposited: 28 May 2012 13:10
Last modified: 15 Mar 2024 02:57
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Contributors
Author:
Lina Happo
Author:
Belinda Phipson
Author:
Jon M. Haga
Author:
Elisa S. Jansen
Author:
Marco J. Herold
Author:
Grant Dewson
Author:
Ewa M. Michalak
Author:
Cassandra J. Vandenberg
Author:
Gordon K. Smyth
Author:
Andreas Strasser
Author:
Suzanne Cory
Author:
Clare L. Scott
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