The role of the bone marrow microenvironment in the establishment and progression of multiple myeloma
Fowler, Jessica Aaron
The interactions between malignant plasma cells and the bone marrow microenvironment are critical for the development of multiple myeloma and the associated osteolytic bone disease. Only recently are studies beginning to elucidate mechanisms by which the altered microenvironment contributes to cancer progression in hematological malignancies. The contributions of the host microenvironment during the initial stages of myeloma development are poorly understood. In the studies presented in this dissertation, we (1) developed a new murine model of myeloma to enable investigation of the host bone marrow microenvironment in myeloma pathogenesis, (2) determined the role of bone marrow stromal cell-derived Dkk1 in myeloma cell establishment and growth, and (3) determined the role of decreased circulating adiponectin in myeloma pathogenesis. Many features of human myeloma bone disease are recapitulated in the well-characterized 5T Radl myeloma model, where transplantation of 5T myeloma cells into recipient mice of the C57Bl/KaLwRij substrain results in propagation of myeloma. Our studies utilized these mice as a tool to provide valuable insights into the development of human myeloma and the associated bone disease. After the initial identification of these factors in the C57Bl/KaLwRij mice, findings in patients, either from the literature or by direct examination of specimens, provide strong support that these changes have clinical relevance. The ultimate goal of this dissertation was to gain a better understanding of the mechanisms that precede myeloma bone disease. Our findings suggest that bone marrow stromal cell-derived Dkk1 and decreases in circulating adiponectin are important in myeloma pathogenesis.