Identification of oncogenic drivers in aggressive B cell Lymphoma by ribosome profiling and a novel primary human lymphocyte transformation assay

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Diffuse Large B Cell Lymphoma (DLBCL) is the most common form of non-Hodgkin Lymphoma. It is an aggressive and devastating form of cancer. Although potentially curable with combination chemotherapy, more than a third of patients will succumb to their disease. Importantly, the incidence of DLBCL increases with age and many older patients are simply unable to tolerate the required chemotherapy. Certain subtypes of DLBCL have been identified that respond particularly poorly to all existing therapies. Thus there is a pressing need for the development of more effective and better tolerated, "targeted" treatments. Over the last decade there have been considerable advances in our understanding of underlying biology of this disease. Much of this has arisen from studies that examine how the activity of cohorts of genes differs between different subtypes of lymphoma. These "gene expression " studies have predominantly examined the total amount mRNA in each cell. mRNA is a messenger molecule that carries instructions from the gene's DNA before being translated in to the final active product, termed the protein. In general more active genes make more mRNA, which is why mRNA has generally been used as a proxy for gene activity. However, recently it has become clear that not all mRNA molecules are "translated" into protein with equal efficiency. Furthermore, a frequent finding in cancer is that certain mRNA molecules that carry instructions advantageous to the cancer may be preferentially translated by the tumor. Recent technology now allows the opportunity to measure the translational rate for each individual mRNA. I will use this technique to identify those mRNAs that are preferentially translated by the different subtypes of DLBCL. Those genes / mRNAs with the greatest changes in translational rate will be tested in cell culture systems to identify those that contribute most to the development and growth of the lymphoma. Ultimately drugs designed to inhibit these genes may prove useful in the treatment of lymphoma. I anticipate that this approach will identify new targets for the development of anti-lymphoma drug treatments. In addition I will investigate the mechanism by which some mRNA is preferentially translated by lymphoma cells. I will use a computational approach to screen preferentially translated mRNA to identify common sequences that the lymphoma cells may use to control the translation. I will then use these sequences as bait to identify the "translation factors' responsible for the altered translation in lymphoma. I will investigate how the activity of these translation factors is controlled, either by lymphoma specific signaling pathways or by mutation. Indeed, mutations have already been identified in factors known to regulate translation in lymphoma cells but the functional significance of these mutations is yet to be investigated.Overall this project will provide a detailed understanding of how lymphoma cells corrupt the normally tightly regulated activity of their genes. In doing so this project may reveal opportunities for new forms of targeted treatment in lymphoma. In addition much of what we learn about the mechanisms of corrupted translational regulation in lymphoma may prove to be of broader relevance to other diseases, in particular other types of cancer.