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Title: Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation
Authors: 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 J.
Stevenson, Freda K.
Forconi, Francesco
Coldwell, Mark J.
Packham, Graham
First Published: 28-Jan-2016
Publisher: American Society of Hematology
Citation: Blood, 2016, 127 (4), pp. 449-457
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.
DOI Link: 10.1182/blood-2015-07-660969
ISSN: 0006-4971
eISSN: 1528-0020
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2016 by The American Society of Hematology. Deposited with reference to the publisher’s archiving policy available on the SHERPA/RoMEO website.
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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