LYMPHOID NEOPLASIA Inhibiting CARD 11 translation during BCR activation by targeting the eIF 4 A RNA helicase

During B-lymphocyte development, antigen engagement of the B-cell receptor (BCR) propagates signals promoting cell growth, survival, andmaturation. Naı̈ve follicular B cells expressmembranebound immunoglobulins of the immunoglobulin (Ig)M and IgD isotype, which rely on the associated Iga and Igb for signal transduction. On T cell-dependent antigen-induced activation within the germinal center (GC), most B cells undergo isotype switching, mainly to IgG, and differentiate into Ig-secreting plasma cells or memory B cells. T-cell help is oftenmediated throughCD40, which serves as a costimulatory signal for B-cell growth, somatic hypermutation, and isotype switching. GC-B and memory B cells that express IgG, which has a much longer cytoplasmic tail than IgM and IgD, displaymore robust signaling onBCR activation, including higher levels of mitogen-activated protein kinase and calcium signaling, than naı̈ve IgM-expressing B cells, although the precise mechanistic differences between IgGand IgM-mediated signals are still debated. Diffuse large B-cell lymphomas (DLBCLs), representing the most common lymphoid malignancy in adults, derive from antigen-experienced B cells. DLBCLs with a more aggressive phenotype often commandeer BCR signaling in an antigen-independent fashion, and the BCR isotype is well correlated with B-cell lymphoma subtypes and disease progression. Although several oncogenes are often dysregulated in DLBCL, the mechanism that links BCR signaling, elevated oncoprotein expression, and lymphoma progression remains unknown. Signaling through the BCR triggers the activation of downstream pathways includingRas/Raf/MEK/Erk,AKT/MTOR, andp70s6K. MTORC1 phosphorylates and releases eIF4E-binding proteins (4EBPs), allowing eIF4E to bind eIF4G and the mRNA cap. Another substrate ofMTORC1 is p70s6K, which enhances the RNA helicase activity of eIF4A by phosphorylating EIF4B, allowing it to subsequently bind eIF4A. p70s6K also phosphorylates the eIF4A inhibitor PDCD4, which results in its bTRCP-mediated ubiquitination and degradation, freeing eIF4A for mRNA binding and cap-complex formation. Significantly, 86% of PDCD4 mice succumb toB-cell lymphomas. Furthermore, gene expression analysis of different B-cell compartments demonstrated that GC B cells have markedly repressed PDCD4 expression. A recent study demonstrated that the eIF4A cofactor,EIF4B, is overexpressed in DLBCL and results in the selective upregulation of mRNAs encoding antiapoptotic and DNA repair proteins. Conversely, the eIF4A inhibitors Hippuristanol and Silvestrol have shown a large degree of B-cell specificity and promise in treating B-cell malignancies.