silvestrol and Lymphoma--Large-B-Cell--Diffuse

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, 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.

Topics: 5' Untranslated Regions; Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Apoptosis Regulatory Proteins; B-Cell CLL-Lymphoma 10 Protein; B-Lymphocytes; Blotting, Western; CARD Signaling Adaptor Proteins; Caspases; Cell Line, Tumor; Cells, Cultured; DEAD-box RNA Helicases; Eukaryotic Initiation Factor-4A; Guanylate Cyclase; Humans; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; Neoplasm Proteins; Protein Biosynthesis; Receptors, Antigen, B-Cell; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinases, 70-kDa; RNA-Binding Proteins; Signal Transduction; Triterpenes