B-cell lymphoma is a significant clinical problem that is rising in incidence and prevalence as the American population ages. The most common subtype of B-cell lymphoma, diffuse large B-cell lymphoma, is a disease which arises from mature B-cells at various stages of antigenic activation and differentiation into plasma cells. Recently, it has become apparent that microRNAs (miRNAs), small RNA molecules that regulate gene expression, are intimately involved in oncogenesis and developmental regulation. In the parent R01, we had proposed to examine how miRNAs act to modulate the activation and oncogenic transformation of B-cells. The three aims were to (i) Identify and characterize microRNA-dependent regulation of B-cell activation and terminal differentiation;(ii) Characterize B-lymphomagenesis as a function of tumor-suppressor microRNAs;and (iii) Characterize the molecular mechanisms of miRNA-mediated regulation in B-cell development and B- cell lymphoma. Since the original grant submission, we have found that the microRNA miR-146a, a feedback regulator of the NFkB pathway, shows a highly important role in B-cell responses to antigenic stimulation. Although the overall role for miR-146a is as a factor that restrains activation of B-cells, individual B-cells show heterogeneity in the developmental decision following activation: proliferation/ differentiation, or cell death. Here, we hypothesize that miR-146a regulates heterogeneity in the expression of critical targets that guide the cell fate decisions of individual B-cells. Recently, the laboratory of Dr. Alexander Hoffmann, an eminent computational and experimental biologist with expertise in the NFkB pathway, has utilized a sophisticated microscopy and modeling system to follow how these developmental decisions are made at the level of individual B-cells. In collaboration with their laboratory, we plan to further analyze the role of miR-146a in B- cell activation by answering the following questions: (i) do single B-cells from miRNA deficient mice show different developmental trajectories during activation? (ii) How does miR-146a regulate the transcriptome of a single B-cell during activation? And (iii) what is the relationship between miRNA activity and the decision of a B-cell to grow and divide or to undergo apoptosis? The answers to these questions will allow us to understand whether miRNAs make a unique and biologically non-redundant contribution to developmental regulation. Furthermore, we will model NFkB activity during B-cell development and how it is regulated by miR-146a. These studies will help us develop predictive models of cell-fate and developmental decisions, which will inform both basic research and therapeutic applications for small RNA techniques. All of the necessary methodology, training, resources, mentorship and personnel are in place for the successful completion of these goals. The completion of these goals promises to significantly increase our understanding of critical biological and pathological processes, in turn leading to improvements in cancer diagnosis and treatment.
ALTH B-cell non-Hodgkin lymphoma is a significant health problem in the United States and its incidence has increased dramatically in the past 30 years. This proposal seeks to bring together remarkable progress in microRNA research with this important disease to solve problems in diagnosis and pathogenesis. Successful completion of this proposal will yield new approaches to lymphoma diagnosis, classification and therapy, and will improve the lives of countless Americans who suffer from B-cell non-Hodgkin lymphoma.
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