Multiple myeloma is a universally fatal disease characterized by the accumulation of malignant plasma cells in the bone marrow. Interleukin 6 (IL-6) promotes normal B lymphocyte differentiation into plasma cells, but is ineffective in supporting B cell growth. In contrast, IL-6 is a potent growth factor for malignant plasma cells in patients with aggressive multiple myeloma. In addition, whereas normal plasma cells no longer express IL-6, evidence suggests that expression of IL-6 in malignant plasma cells may be deregulated. Currently, there is no effective treatment for this disease. Because myeloma cells display an aberrant proliferative response to IL-6, it is crucial to identify the molecular changes that result in deregulation of IL-6 expression during malignant transformation. We have established a panel of new human myeloma cell lines that exhibit phenotypes representative of myeloma cells isolated from patients with aggressive disease, i.e., proliferation in response to IL-6. We have demonstrated that our panel of myeloma cell lines and primary cultures of patient myeloma cells express CD40, an important cell surface receptor in normal B cells, that has been reported to be absent in plasma cells. Moreover, CD40 stimulation of myeloma cell lines results in enhanced proliferation. In this proposal, we hypothesize that CD40 stimulation contributes to myeloma cell proliferation by inducing the autocrine production of IL-6. We also hypothesize that this pathway becomes available to the tumor cell as a result of loss or alteration of transcriptional control of the IL-6 gene during tumor progression. We have, therefore, proposed 3 specific aims to test these hypotheses.
In Specific Aim #1, we will attempt to block CD40 stimulated proliferation of myeloma cells with anti-IL-6 neutralizing antibodies and determine the effects of anti-CD40 stimulation on transcription of the IL-6 gene.
In Specific Aim #2, we will systematically test which elements in the IL-6 promoter are crucial in allowing CD40 stimulated transcription of the IL-6 gene.
In Specific Aim #3, we will extend our studies of the proposed link between CD40 and IL-6 to patients' cells by examining expression levels of CD40 and CD40 ligand and determining the effects of CD40 stimulation on IL-6 expression. Utilization of the invaluable myeloma cell line panel for the proposed in vitro studies, and extension of these studies to myeloma patient samples, will provide much needed insight into the regulation of IL-6 expression in myeloma cells.
|Mihalcik, Stephen A; Huddleston 3rd, Paul M; Wu, Xiaosheng et al. (2010) The structure of the TNFRSF13C promoter enables differential expression of BAFF-R during B cell ontogeny and terminal differentiation. J Immunol 185:1045-54|