Loren D. Erickson, PhD
Plasma cell malignancies
Plasma cells (PC) are specialized B cells that are exquisitely designed for the sole purpose of providing the host with long-term antibody protection. As such, PCs themselves are long-lived, which is an asset for protective humoral immunity but is a liability in PC malignancies such as multiple myeloma (MM). MM is characterized by the continual accumulation of PCs within the bone marrow that ultimately shut down hematopoiesis and bone development. At present, there is no cure for MM and virtually all patients relapse after treatment with conventional therapies.
Although some secreted factors, such as IL-6, and membrane-bound proteins like the adhesion molecule, VLA-4, have been shown to participate in the maintenance of MM, the factors central to the growth and survival of MM progenitors have yet to be identified. We have identified a rapidly growing, self-renewing, post-germinal center B cell population -- present in low numbers in the bone marrow -- as the precursors to normal plasma cells (PCpre). These cells can undergo self-renewal or can terminally differentiate to very long-lived PCs. They exhibit striking similarities to the putative stem cell in MM. The inextricable link between the bone marrow microenvironment and the persistence of MM cells has drawn our attention to a newly-identified member of the TNF receptor family, B cell maturation antigen (BCMA), that we have shown to be critical for the survival of normal long-lived bone marrow PCs. Signaling through BCMA may control PCpre self-renewal as well as their transformation to MM progenitors. We therefore hypothesize that the PCpre is the normal counterpart of the MM progenitor, and that alterations in the normal cell survival, growth, or differentiation pathways occur as PCpre undergo conversion to MM. We are currently testing this hypothesis in the laboratory by addressing three specific aims: 1. To identify the BM stromal elements that control PCpre self-renewal. 2. To determine the BM cells and relevant ligand, BAFF and/or APRIL, that support PC survival. 3. To investigate whether BAFF/APRIL promote MM growth by regulating cell cycle gene expression and MM survival by regulating anti-apoptotic factors.
Study of the novel PCpre cell type will identify the factors that control self-renewal and will unlock the key to understanding how MM stem cells are sustained. The intrinsic mechanisms of how the survival ligands, BAFF/APRIL, control MM growth and survival will also be elucidated. Together, these will significantly aid in the development of more effective strategies in the treatment of MM.