DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a cancer in the bone marrow (BM) characterized by the accumulation of transformed plasma cells (PCs). MM is the second most common hematologic malignancy after non-Hodgkin lymphoma, with approximately 20,000 new cases diagnosed yearly in the United States. Currently, MM is an incurable disease, leading to nearly 11,000 deaths per year. The lack of better therapeutic options for the treatment of this disease is in part a reflection of the poor understanding of MM pathophysiology. As the understanding of disease often relies on knowledge surrounding the normal tissue counterpart, we believe that the limited knowledge of normal PC biology creates a source of hindrance to the study of MM. To this end, we propose a project to examine both normal and malignant PCs and factors that may contribute to their survival and proliferation in the human BM microenvironment. A recent study identified eosinophils as having a survival- promoting role for normal BM PCs in mice through their secretion of cytokines such as interleukin 6 (IL-6) and a proliferation inducing ligand (APRIL). We hypothesize that, in the human BM, eosinophils may similarly enhance normal PC longevity. Additionally, we hypothesize that MM pathophysiology may be influenced by the presence of eosinophils. In support of these hypotheses, our preliminary data show close association of PCs and eosinophils in the human BM (normal and MM patients). Moreover, in vitro studies indicate that human eosinophils enhance the proliferation of MM cell lines. In the two focused aims proposed in this study, we will further define and characterize the impact of eosinophils in normal and malignant human PC biology. First, we will investigate the molecular mechanism(s) by which eosinophils enhance MM proliferation. We will extend these investigations to examine the role of eosinophils in normal PC homeostasis and function. Lastly, we will utilize a xenograft model to test in vivo the biological role of eosinophils in MM. The results of these studies will provide insight into the maintenance of normal humoral immunity in conjunction with the understanding of MM and the tumor microenvironment. The broader implications of our findings may lead to future development of novel therapeutics for MM by targeting specific components of the tumor microenvironment (i.e. eosinophils) to minimize disease progression. |