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BCR-signaling-induced cell death demonstrates dependency on multiple BH3-only proteins in a murine model of B-cell lymphoma.

BCR-signaling-induced cell death demonstrates dependency on multiple BH3-only proteins in a murine model of B-cell lymphoma.
BCR-signaling-induced cell death demonstrates dependency on multiple BH3-only proteins in a murine model of B-cell lymphoma.
Genetic recombination during B-cell development regularly results in the generation of autoreactive, potentially pathogenic B-cell receptors (BCRs). Consequently, multiple mechanisms link inappropriate BCR specificity to clonal deletion. Similar pathways remain in malignant B cells, offering the potential for targeting BCR signaling. Recently, small molecule inhibitors have realized this potential and, therefore, a deeper understanding of BCR-induced signaling networks in malignant cells is vital. The BH3-only protein Bim has a key role in BCR-induced apoptosis, but it has long been proposed that additional BH3-only proteins also contribute, although conclusive proof has been lacking. Here, we comprehensively characterized the mechanism of BCR-induced apoptosis in E?-Myc murine lymphoma cells. We demonstrate the upregulation of Bim, Bik, and Noxa during BCR signaling in vitro and that intrinsic apoptosis has a prominent role in anti-BCR antibody therapy in vivo. Furthermore, lymphomas deficient in these individual BH3-only proteins display significant protection from BCR-induced cell death, whereas combined loss of Noxa and Bim offers enhanced protection in comparison with loss of Bim alone. Some but not all of these effects were reversed upon inhibition of Syk or MEK. These observations indicate that BCR signaling elicits maximal cell death through upregulation of multiple BH3-only proteins; namely Bim, Bik, and Noxa.Cell Death and Differentiation advance online publication, 17 July 2015; doi:10.1038/cdd.2015.97.
1350-9047
303-312
Carter, M.J.
3baac102-d80c-42ba-ab4d-ad339a48169e
Cox, K.L.
7305c27e-9cdc-4e37-b994-ac55d7d1dfd2
Blakemore, S.J.
1b8f7beb-1d31-4182-b78e-066994e706b2
Bogdanov, Y.D.
0c970999-e191-4f1b-90d9-7bf25a5d5b4b
Happo, L.
bc4c68ba-ec79-48a8-9416-7a499063129f
Scott, C.L.
a3670564-5617-494f-8386-ecee53f76086
Strasser, A.
2fe265c2-1bd2-401a-836e-e4c13ef2a188
Packham, G.K.
fdabe56f-2c58-469c-aadf-38878f233394
Cragg, M.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Carter, M.J.
3baac102-d80c-42ba-ab4d-ad339a48169e
Cox, K.L.
7305c27e-9cdc-4e37-b994-ac55d7d1dfd2
Blakemore, S.J.
1b8f7beb-1d31-4182-b78e-066994e706b2
Bogdanov, Y.D.
0c970999-e191-4f1b-90d9-7bf25a5d5b4b
Happo, L.
bc4c68ba-ec79-48a8-9416-7a499063129f
Scott, C.L.
a3670564-5617-494f-8386-ecee53f76086
Strasser, A.
2fe265c2-1bd2-401a-836e-e4c13ef2a188
Packham, G.K.
fdabe56f-2c58-469c-aadf-38878f233394
Cragg, M.
ec97f80e-f3c8-49b7-a960-20dff648b78c

Carter, M.J., Cox, K.L., Blakemore, S.J., Bogdanov, Y.D., Happo, L., Scott, C.L., Strasser, A., Packham, G.K. and Cragg, M. (2016) BCR-signaling-induced cell death demonstrates dependency on multiple BH3-only proteins in a murine model of B-cell lymphoma. Cell Death and Differentiation, 23 (2), 303-312. (doi:10.1038/cdd.2015.97). (PMID:26184912)

Record type: Article

Abstract

Genetic recombination during B-cell development regularly results in the generation of autoreactive, potentially pathogenic B-cell receptors (BCRs). Consequently, multiple mechanisms link inappropriate BCR specificity to clonal deletion. Similar pathways remain in malignant B cells, offering the potential for targeting BCR signaling. Recently, small molecule inhibitors have realized this potential and, therefore, a deeper understanding of BCR-induced signaling networks in malignant cells is vital. The BH3-only protein Bim has a key role in BCR-induced apoptosis, but it has long been proposed that additional BH3-only proteins also contribute, although conclusive proof has been lacking. Here, we comprehensively characterized the mechanism of BCR-induced apoptosis in E?-Myc murine lymphoma cells. We demonstrate the upregulation of Bim, Bik, and Noxa during BCR signaling in vitro and that intrinsic apoptosis has a prominent role in anti-BCR antibody therapy in vivo. Furthermore, lymphomas deficient in these individual BH3-only proteins display significant protection from BCR-induced cell death, whereas combined loss of Noxa and Bim offers enhanced protection in comparison with loss of Bim alone. Some but not all of these effects were reversed upon inhibition of Syk or MEK. These observations indicate that BCR signaling elicits maximal cell death through upregulation of multiple BH3-only proteins; namely Bim, Bik, and Noxa.Cell Death and Differentiation advance online publication, 17 July 2015; doi:10.1038/cdd.2015.97.

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e-pub ahead of print date: 17 July 2015
Published date: 2016
Organisations: Cancer Sciences

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Local EPrints ID: 385495
URI: http://eprints.soton.ac.uk/id/eprint/385495
ISSN: 1350-9047
PURE UUID: 988930a8-f5a7-4271-b196-a6a4dd3a873e
ORCID for Y.D. Bogdanov: ORCID iD orcid.org/0000-0003-4667-5890
ORCID for G.K. Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for M. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 13 Jan 2016 15:47
Last modified: 17 Jun 2020 00:38

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Contributors

Author: M.J. Carter
Author: K.L. Cox
Author: S.J. Blakemore
Author: Y.D. Bogdanov ORCID iD
Author: L. Happo
Author: C.L. Scott
Author: A. Strasser
Author: G.K. Packham ORCID iD
Author: M. Cragg ORCID iD

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