The long term goal of this proposal is to understand the mechanisms that underlie B cell terminal differentiation and pathogenesis of multiple myeloma. Terminal differentiation of B cells to plasma cells in vivo is tightly coupled to cell cycle arrest and cell death, which limits the humoral response. Multiple myelomas represent a major cancer of the human lymphoid system with no cure. It is characterized by massive accumulation of plasma cells but the molecular basis of its pathogenesis is unknown, due to our lack of understanding of cell cycle control and cell death during normal B cell terminal differentiation. Interleukin-6 (IL-6) has a crucial role in B cell terminal differentiation and neoplasia: it is required for IgG and IgA responses and generation of plasmacytomas in mice, closely resembling human multiple myelomas. When ectopically expressed, IL-6 alone is sufficient to induce IgG1 plasmacytomaor plasmacytosis according to the strain of mouse. The mechanism for B cell terminal differentiation has been examined only in IL-6-differentiation of human IgG+ lymphoblastoid cells in vitro, in which cell cycle arrest was mediated by the cyclin dependent kinase inhibitor p18ink4c and apoptosis was modulated by an antiapoptotic gene Mcl-1. Accumulation of non-cycling plasmacytoma cells was preceded by a marked expansion of activated B cells. The major objective of this study is to confirm the hypothesis whereby plasmacytoma cells arise from deregulation of cell cycle control during B cell activation and failure to undergo apoptosis, by elucidation of the mechanisms that govern cell cycle control and apoptosis during terminal differentiation. Taking advantage of an in vivo primary B cell terminal differentiation system and mice overexpressing IL-6 or deficient in various CDK inhibitors and caspase-3 genes, the PI proposes to 1) elucidate the mechanisms for cell cycle control during B cell activation and expansion of activated B cells in plasmacytomagenesis; 2) characterize the genes expressed on primary plasma cells and plasmacytoma cells that are potentially relevant to cell cycle control and apoptosis; and 3) investigate the mechanism for apoptosis and survival in primary plasma and plasmacytoma cells.
