Plasma cell neoplasms (PCN), including multiple myeloma, are tumors of terminally differentiated B cells. Despite a significant research effort, and numerous advances in therapy, most tumors of this B cell lineage remain incurable. To this end, understanding factors which are critical for the development of PCN may lead to new avenues for therapy. Interleukin-6 (IL-6) is a pleiotropic, pro-inflammatory cytokine which supports the growth, proliferation, and survival of myeloma cells.;We found that inflammation, and in particular, IL-6 is critical for the development of PCN. In order to determine if tumor microenvironment (TME) or B cell-derived IL-6 was more important in PCN development, we utilized an adoptive transfer system of tumor formation. By adoptively transferring premalignant B cells into recipients, and then providing the B cells with an inflammatory microenvironment through the use of pristane, we were able to generate donor tumors in recipient mice. Utilizing this method, a series of adoptive transfers were performed to determine the primary source of IL-6 in murine PCN development. We discovered that TME-derived IL-6, and not B cell-derived IL-6, is most critical for PCN development.;Furthermore, in studying the lesions in B cell development which lead to tumor formation, we discovered that IL-6 collaborates with the proto-oncogene c-Myc in spontaneous germinal center (GC) formation. The spontaneous GCs were accompanied by a robust follicular T helper cell response. In characterizing the genetic lesions which lead to the GC formation, we discovered that Myc-transgenic mice develop a significant increase in the population of B1a B cells. Furthermore, these B1a B cells infiltrate the spontaneous GCs of double transgenic Myc/IL-6 mice. Lastly, utilizing our adoptive transfer method, we determined that the germinal center response is necessary for the development of PCN in mice.;Lastly, we focused our efforts on another oncogene which collaborates with IL-6, BCL-2. Double transgenic BCL-2/IL-6 mice develop PCN and spontaneous GCs. Of interest however, the adoptive transfer of BCL-2/IL-6 B cells results in tumor formation without the use of pristane. Furthermore, the adoptive transfer recipients develop bone lesions, hind limb paralysis, and a monoclonal gammopathy. This model closely recapitulates many of the pathophysiological features seen in human PCN. This new model promises to be important for future studies into PCN development and treatment. |