THE ROLE OF FBXO45 IN DIFFUSE LARGE B-CELL LYMPHOMA PATHOGENESIS Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma and represents the most common form of malignant lymphoma in the western hemisphere. The biologic events underlying the pathogenesis of DLBCL are not completely understood. We have recently identified functional inactivation of FBXO45, an E3 ubiquitin ligase in DLBCL. In this application, we will utilize transgenic mouse models to explore the biological roles for FBXO45 in B-cell differentiation and lymphomagenesis. Further, we will employ biochemical and molecular biology techniques to better understand the role FBXO45 in the pathogenesis of DLBCL. Accordingly, we propose in the first aim of this application to utilize newly created transgenic mouse models to functionally interrogate the role of FBXO45 in B- cell development and lymphomagenesis. In the second aim, we will identify the global cellular substrates of FBXO45 in B cell contexts. These studies will establish the role of FBXO45 in the pathogenesis of DLBCL and establish the mechanisms by which its deregulation contributes to DLBCL.
Deregulation of ubiquitin ligases and their substrates is increasingly being recognized to play a significant role in the pathogenesis of cancer. In this proposal, we will investigate the involvement of a ubiquitin ligase known as FBXO45 in the development of diffuse large B-cell lymphoma, the most frequent form of lymphoma death in the U.S. Our studies will lead to a better understanding of the function of FBXO45 and offer insights into novel therapeutic strategies for treatments of DLBCL.