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. This proposal outlines a 5-year research plan to unravel the role of two tumor- suppressor miRNAs, miR-34a and miR-146a, in B-cell lymphoma pathogenesis, to understand their developmental roles in B-cell activation and to evaluate their mechanism of action. We propose the following hypotheses: (i) miR-34a and miR-146a regulate B-cell activation and plasma cell differentiation (ii) Dysregulation of these two miRNAs contributes to the pathogenesis of B-cell malignancies and (iii) the mechanism of their action in both development and malignancy relates to their regulation of several critical targets. We will use a combination of genetically defined murine models, retroviral transduction systems, bone marrow transplantation, high-throughput approaches, bioinformatics, and hypothesis-driven investigation of individual targets to understand the role of miRNAs in development and oncogenesis. This proposal is eminently translational and future directions include the development of diagnostic and therapeutic applications of miRNAs. 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. Perhaps most importantly, it will bring forward a highly promising approach to treatment of patients who suffer from devastating malignant diseases of B-cells.
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.
|Wallace, Jared A; Kagele, Dominique A; Eiring, Anna M et al. (2017) miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response. Blood 129:3074-3086|
|Li, Bo; Wang, Xi; Choi, In Young et al. (2017) miR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity. J Clin Invest 127:3702-3716|
|King, Jennifer K; Ung, Nolan M; Paing, May H et al. (2016) Regulation of Marginal Zone B-Cell Differentiation by MicroRNA-146a. Front Immunol 7:670|
|Palanichamy, Jayanth Kumar; Tran, Tiffany M; Howard, Jonathan M et al. (2016) RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation. J Clin Invest 126:1495-511|
|Contreras, Jorge R; Palanichamy, Jayanth Kumar; Tran, Tiffany M et al. (2015) MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1. Oncotarget 6:11023-37|
|Hu, Ruozhen; Kagele, Dominique A; Huffaker, Thomas B et al. (2014) miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity 41:605-19|