FCRL Regulation in B Cell Tolerance and Malignancy

About This Grant

PROJECT SUMMARY B lineage cells are responsible for greater than 85% of non-Hodgkin’s lymphomas (NHL), including the most prevalent leukemia in Western countries, chronic lymphocytic leukemia (CLL). Recent studies of lymphoprolifer- ative disorders and CLL have highlighted their dependence on the B cell receptor (BCR) and its signaling com- plex. Numerous co-receptors are integrated with and are capable of modulating BCR responses. Immunothera- peutic targeting of discrete B cell surface regulatory proteins (e.g., CD19, CD20) and selective inhibition of critical signaling pathways is dramatically shifting our approach to the care of individuals with this class of malignancies. However, emerging resistance to antibody and cellular immunotherapies as well as small molecule inhibitors in patients over time limits these therapies. The development of strategies to address these issues is impeded by gaps in knowledge concerning how B cells differentially regulate BCR signals at homeostasis versus activation, what factors become proximally dysregulated to drive disease pathology and progression, and the mechanisms underlying maintenance of transformed B cells. Members of the Fc receptor-like gene family (FCRL1-5) encode cell surface receptors with complex tyrosine-based regulation that are preferentially expressed by B cells. Their significance as mediators of B cell pathology, and thus as potential therapeutic targets, is indicated by their asso- ciations with human lymphoproliferative, autoimmune, infectious, and immunodeficiency disorders. The long- term objective of our studies is to determine the mechanistic roles of FCRL molecules in B cell pathology and reveal their therapeutic potential. Importantly, FCRL1 is a pan B cell marker overexpressed by CLL and many other mature B cell malignancies and correlates with disease aggression in NHL. While it is uniquely positioned among human and mouse FCRL members in terms of enhancing BCR activation, new findings indicate FCRL1 exhibits context-dependent regulation. Our hypothesis is that FCRL1 harbors tyrosine-based properties that differentially regulate B cell responses, but when dysregulated influence the pathogenesis of lymphoproliferative and autoimmune disorders. Based on supportive preliminary data, in Aim 1, we will determine the influence of FCRL1 on B cell responses in human and mouse disease models of CLL and tolerance. In Aim 2, we will dissect the mechanisms underlying FCRL1 signaling and its B cell regulation. In Aim 3, we will investigate conserved in vivo roles for FCRL1 by employing new physiologic models. The proposed studies are anticipated to have broad implications that advance the understanding of B cell signaling by focusing on a remarkably understudied surface receptor and a novel regulatory axis. Our findings will be translationally relevant by providing insights into control mechanisms influencing B cell malignancy and tolerance with the promise of advancing novel therapeutic strategies capable of modulating or targeting this axis.