Deregulation of gene expression at the level of translation in diffuse large B-cell lymphoma


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Anne Willis1
1MRC Toxicology Unit, Leicester, UK

Abstract

Deregulation of gene expression at the level of translation makes a major contribution to both cancer development and progression although few studies have been performed on tumour samples to identify the full spectrum of mRNAs that are deregulated via this route. To investigate translational dysregulation in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) polysome profiling was performed to identify mRNAs that are polysomally associated, in parallel with microRNA (miRNA) profiling as these short non-coding RNAs negatively regulate translation by binding to targets within the 3’ UTR of their cognate mRNAs. We show that proteins that function in apoptosis including, DAXX, BCL-2, c-Myc, BCL-XL, and DNA damage namely BRCA1, BRCA2, ERCC5 are translationally deregulated in FL/DLBCL with large changes in protein expression and no alteration in the level of the corresponding mRNAs. Mechanistically we show that translational deregulation is mediated by a combination of altered miRNA expression and deregulated expression of the canonical initiation factor eIF4B. We show that there is an inverse correlation between translational up-regulation of specific mRNAs and decreased expression of those miRNAs which have the potential to target these mRNAs in DLBCL/FL. For example, we show that there is a decrease expression of miR146 and miR34a that target c-Myc and BRAC1 respectively. Over-expression of eIF4B also makes a significant contribution to tumorigenesis by stimulating the translation of mRNAs that contain highly structured 5’ UTRs including those that encode survival proteins and proto-oncogenes. Finally, we show that by combining translational profiling and miRNA expression data it is possible to provide a new way in which to predict patient survival and influence treatment options for subgroups of patients.