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Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation.

Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation.
Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation.
Antigenic stimulation via the B-cell receptor (BCR) is a major driver of the proliferation and survival of chronic lymphocytic leukemia (CLL) cells. However, the precise mechanisms by which BCR stimulation leads to accumulation of malignant cells remain incompletely understood. Here, we investigated the ability of BCR stimulation to increase messenger RNA (mRNA) translation, which can promote carcinogenesis by effects on both global mRNA translation and upregulated expression of specific oncoproteins. Re-analysis of gene expression profiles revealed striking upregulation of pathways linked to mRNA translation both in CLL cells derived from lymph nodes, the major site of antigen stimulation in vivo, and after BCR stimulation in vitro. Anti-IgM significantly increased mRNA translation in primary CLL cells, measured using bulk metabolic labeling and a novel flow cytometry assay to quantify responses at a single-cell level. These translational responses were suppressed by inhibitors of BTK (ibrutinib) and SYK (tamatinib). Anti-IgM-induced mRNA translation was associated with increased expression of translation initiation factors eIF4A and eIF4GI, and reduced expression of the eIF4A inhibitor, PDCD4. Anti-IgM also increased mRNA translation in normal blood B cells, but without clear modulatory effects on these factors. In addition, anti-IgM increased translation of mRNA-encoding MYC, a major driver of disease progression. mRNA translation is likely to be an important mediator of the growth-promoting effects of antigen stimulation acting, at least in part, via translational induction of MYC. Differences in mechanisms of translational regulation in CLL and normal B cells may provide opportunities for selective therapeutic attack.
0006-4971
449-457
Yeomans, Alison
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Thirdborough, Stephen M.
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Valle-Argos, Beatriz
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Linley, Adam
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Krysov, Sergey
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Hidalgo, Marina Sanchez
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Leonard, Elodie
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Ishfaq, Muhammad
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Wagner, Simon D.
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Willis, Anne E.
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Steele, Andrew
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Stevenson, Freda
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Forconi, Francesco
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Coldwell, Mark J.
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Packham, Graham
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Yeomans, Alison
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Thirdborough, Stephen M.
161784fb-c8e3-4beb-86b1-cd8bc8ddf8de
Valle-Argos, Beatriz
4fddaa71-c0aa-4b95-b464-8bdb592428a2
Linley, Adam
10879190-27e3-42a9-a28b-3f8d7724e439
Krysov, Sergey
3a78eac1-af40-4b37-8576-3462947649be
Hidalgo, Marina Sanchez
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Leonard, Elodie
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Ishfaq, Muhammad
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Wagner, Simon D.
39ec1b3c-2102-4aec-a2ab-e55c8e6e1662
Willis, Anne E.
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Steele, Andrew
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Stevenson, Freda
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Forconi, Francesco
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Coldwell, Mark J.
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Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

Yeomans, Alison, Thirdborough, Stephen M., Valle-Argos, Beatriz, Linley, Adam, Krysov, Sergey, Hidalgo, Marina Sanchez, Leonard, Elodie, Ishfaq, Muhammad, Wagner, Simon D., Willis, Anne E., Steele, Andrew, Stevenson, Freda, Forconi, Francesco, Coldwell, Mark J. and Packham, Graham (2016) Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation. Blood, 127 (4), 449-457. (doi:10.1182/blood-2015-07-660969). (PMID:26491071)

Record type: Article

Abstract

Antigenic stimulation via the B-cell receptor (BCR) is a major driver of the proliferation and survival of chronic lymphocytic leukemia (CLL) cells. However, the precise mechanisms by which BCR stimulation leads to accumulation of malignant cells remain incompletely understood. Here, we investigated the ability of BCR stimulation to increase messenger RNA (mRNA) translation, which can promote carcinogenesis by effects on both global mRNA translation and upregulated expression of specific oncoproteins. Re-analysis of gene expression profiles revealed striking upregulation of pathways linked to mRNA translation both in CLL cells derived from lymph nodes, the major site of antigen stimulation in vivo, and after BCR stimulation in vitro. Anti-IgM significantly increased mRNA translation in primary CLL cells, measured using bulk metabolic labeling and a novel flow cytometry assay to quantify responses at a single-cell level. These translational responses were suppressed by inhibitors of BTK (ibrutinib) and SYK (tamatinib). Anti-IgM-induced mRNA translation was associated with increased expression of translation initiation factors eIF4A and eIF4GI, and reduced expression of the eIF4A inhibitor, PDCD4. Anti-IgM also increased mRNA translation in normal blood B cells, but without clear modulatory effects on these factors. In addition, anti-IgM increased translation of mRNA-encoding MYC, a major driver of disease progression. mRNA translation is likely to be an important mediator of the growth-promoting effects of antigen stimulation acting, at least in part, via translational induction of MYC. Differences in mechanisms of translational regulation in CLL and normal B cells may provide opportunities for selective therapeutic attack.

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Accepted/In Press date: 15 October 2015
e-pub ahead of print date: 21 October 2015
Published date: 28 January 2016
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 394384
URI: http://eprints.soton.ac.uk/id/eprint/394384
ISSN: 0006-4971
PURE UUID: a544d5fc-9298-4229-832c-3bb97a7e0943
ORCID for Andrew Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Freda Stevenson: ORCID iD orcid.org/0000-0002-0933-5021
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831
ORCID for Mark J. Coldwell: ORCID iD orcid.org/0000-0002-6243-3886
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 16 May 2016 11:16
Last modified: 15 Mar 2024 03:41

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Contributors

Author: Alison Yeomans
Author: Beatriz Valle-Argos
Author: Adam Linley
Author: Sergey Krysov
Author: Marina Sanchez Hidalgo
Author: Elodie Leonard
Author: Muhammad Ishfaq
Author: Simon D. Wagner
Author: Anne E. Willis
Author: Andrew Steele ORCID iD
Author: Freda Stevenson ORCID iD
Author: Mark J. Coldwell ORCID iD
Author: Graham Packham ORCID iD

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