Document Type

Dissertation

Date of Degree

Fall 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In

Immunology

First Advisor

Siegfried Janz

Second Advisor

Thomas J. Waldschmidt

Abstract

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.

Public Abstract

Plasma cell neoplasia makes up over two percent of all newly-diagnosed tumors in the United States, and over one percent of all cancer-related deaths. While a great deal of research has been done on these tumors, they remain incurable. A bottleneck in developing new and exciting therapies is the lack of a reliable way to test therapies in a live organism. Therefore, the lack of an animal model for plasma cell neoplasia represents an unmet medical need.

Our lab focuses on the development of animal models for plasma cell neoplasia. My work focuses on the role of interleukin 6 in plasma cell neoplasia development. We have determined that in, in mice, interleukin 6 is necessary for plasma cell neoplasia development. In addition, it is the bystander cells in the tumor which are the main source of interleukin 6. Our work may have direct implications for targeting plasma cell neoplasia development in humans.

Keywords

publicabstract

Pages

xiii, 132 pages

Bibliography

Includes bibliographical references (pages 113-132).

Copyright

Copyright 2014 Timothy Robert Rosean

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