ROLE OF CYTOKINES IN THE PATHOGENESIS OF MONOCLONAL GAMMOPATHIES

Objective: To review data that postulate a role for cytokines and oncogenes in the pathogenesis of monoclonal gammopathies. Design: Published studies that provide evidence of the clinical progression of normal B cells to monoclonal gammopathy of undetermined significance (MGUS) to active myeloma are discussed. Results: On the basis of mouse plasmacytoma models, increased expression of c-myc in B lymphocytes may be the initial oncogenic event that leads to MGUS in humans. Over time, this monoclonal subpopulation may acquire additional genetic abnormalities, such as aberrant interleukin (IL) 1 beta expression. Because IL 1 beta has potent osteoclast activating factor activity, increased production of IL 1 beta by monoclonal plasma cells may be the genetic event responsible for the progression of MGUS to myeloma. The in vivo plasma cell labeling index (proliferative rate) is the most powerful prognostic factor in patients with myeloma. The proliferative compartment observed in myeloma may parallel normal B-cell development because cytoplasmic immunoglobulin-positive cells with the ability to proliferate exist normally. With continued progression of disease, the ratio of proliferating monoclonal plasmablasts to nonproliferating monoclonal plasma cells may increase under the influence of cytokines such as IL 6. Conclusion: A more complete understanding of the basic biologic features of myeloma should lead to innovative therapies in the future.