Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase

James J. Steinhardt, Raymond J. Peroutka, Krystyna Mazan-Mamczarz, Qing Chen, Simone Houng, Carol Robles, Rolf N. Barth, Joseph DuBose, Brandon Bruns, Ronald Tesoriero, Deborah Stein, Raymond Fang, Nader Hanna, Jason Pasley, Carlos Rodriguez, Mark D. Kligman, Matthew Bradley, Joseph Rabin, Stacy Shackelford, Bojie DaiAri L. Landon, Thomas Scalea, Ferenc Livak, Ronald B. Gartenhaus*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5′ untranslated region (UTR). Oncogenes with complex 5′UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5′UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G+ splenic B cells, fromwhichmost DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM+ B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas.

Original languageEnglish (US)
Pages (from-to)3758-3767
Number of pages10
JournalBlood
Volume124
Issue number25
DOIs
StatePublished - Dec 11 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Steinhardt, J. J., Peroutka, R. J., Mazan-Mamczarz, K., Chen, Q., Houng, S., Robles, C., Barth, R. N., DuBose, J., Bruns, B., Tesoriero, R., Stein, D., Fang, R., Hanna, N., Pasley, J., Rodriguez, C., Kligman, M. D., Bradley, M., Rabin, J., Shackelford, S., ... Gartenhaus, R. B. (2014). Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase. Blood, 124(25), 3758-3767. https://doi.org/10.1182/blood-2014-07-589689