Article title: Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase Short title: BCR activation enhances eIF4A activity

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 upon B-cell receptor (BCR) mediated p70s6K activation, PDCD4 is degraded and eIF4A activity is greatly enhanced. We have identified a subset of genes involved in BCR signaling, including CARD11, BCL10 and MALT1, which have complex 5’UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced upon BCR activation, and is attenuated by the eIF4A inhibitor, Silvestrol. Antigen-experienced IgG splenic B-cells, from which most 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. For personal use only. on November 1, 2017. by guest www.bloodjournal.org From