Our research has focused on understanding the genetic basis and pathogenesis of Waldenstr痴 Macroglobulinemia (WM), and the development of therapeutics for this B-cell malignancy which effects 6,000-10,000 patients a year in the United States. As part of these efforts, we recently characterized the existence of a familial form of Waldenstr痴 Macroglobulinemia, describing its incidence, clinical, laboratory and cytogenetic characteristics. Importantly as part of these efforts, we demonstrated differing patterns of gene losses among WM patients including BLIMP1, PAX5 and members of the unfolded protein response (UPR) including XBP1 and IRE1a. Most recently our studies have underscored that patients with WM have constitutive IgA and IgG hypogammaglobulinemia and mutations in APRIL and its signaling receptor TACI akin to those found in patients with Common Variable Immunodeficiency Syndrome (CVID), underscoring that CVID may serve as a predisposition to WM. We have also focused our studies on understanding what genetic mechanisms underscore the loss of homeostasis in WM by demonstrating the cell surface loss of CD27 and its adapter molecule SIVA which are regulated by soluble and cell surface CD70 presented by immunoregulatory cells including T- and mast cells. Our studies have also gained important insight into the pathogenesis of Waldenstr痴 Macroglobulinemia by demonstrating a role for the excess mast cells found in the bone marrows of patients with WM. We recently demonstrated that mast cells serve as potent inducers of growth and enhancers of tumor cell survival through a host of mediators including CD40 ligand, A proliferation inducing ligand (APRIL), B-lymphocyte stimulator (B-LYS) protein, platelet derived growth factor (PDGFa) and vascular endothelial growth factor (VEGF), while also showing that WM tumor cells through soluble CD27 induce expression of several of these ligands. These revelations have helped in the development of novel therapeutic strategies targeting mast cells and mast-cell-tumor cell interactions in WM. In addition to the above studies, we have also sought to advance the therapy for WM by conducting clinical trials utilizing monoclonal antibodies, as single agents and in combination with nucleoside analogs, cytotoxic agents, and immunomodulating agents, as well as phosphodiesteraase and proteosome inhibitors. As part of these efforts we have defined in our lab the mechanisms of action and resistance for these agents, and in particular the role of Fc gamma receptor polymorphisms in predicting clinical responses to the CD20 directed monoclonal antibody rituximab. The above work has established several novel agents for the therapy of WM, while ongoing trials are being conducted to enhance the efficacy toxicity.