A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma

Horvilleur, E. et al. (2014) A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma. Leukemia, 28(5), pp. 1092-1102. (doi: 10.1038/leu.2013.295) (PMID:24135829) (PMCID:PMC4017261)

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Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5′-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Bushell, Professor Martin
Authors: Horvilleur, E., Sbarrato, T., Hill, K., Spriggs, R.V., Screen, M., Goodrem, P.J., Sawicka, K., Chaplin, L.C., Touriol, C., Packham, G., Potter, K.N., Dirnhofer, S., Tzankov, A., Dyer, M.J.S., Bushell, M., MacFarlane, M., and Willis, A.E.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Leukemia
Publisher:Springer Nature
ISSN (Online):1476-5551
Published Online:18 October 2013
Copyright Holders:Copyright © 2014 Macmillan Publishers Limited
First Published:First published in Leukemia 28(5): 1092-1102
Publisher Policy:Reproduced under a Creative Commons License

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