Elsawa, Sherine F.
M.S. (Master of Science)
Department of Biological Sciences
Immunology; Cellular biology; Oncology; Immunology; Cytology; Oncology
Immunoglobulin (Ig) secretion by terminally differentiated B cells is an important component of the immune response to foreign pathogens. Its over-production is a defining characteristic of many B cell malignancies including Waldenstrom macroglobulinemia (WM), where elevated levels of IgM is associated with significant morbidity and poor prognosis. Therefore, the identification and characterization of the mechanisms controlling Ig secretion are of great importance for the development of future therapeutic approaches for this disease. Here, we define a novel pathway involving the oncogenic transcription factor GLI2 which modulates IgM secretion by WM malignant cells. Pharmacological and genetic inhibition of GLI2 but not the other GLI transcription factor family members, GLI1 and GLI3, resulted in a reduction in IgM secretion. Screening for a mechanism identified the IL-6 receptor alpha subunit (IL-6Ralpha/gp80) as a downstream target of GLI2 mediating the regulation of IgM secretion. Using a combination of expression, luciferase and chromatin immunoprecipitation assays we demonstrate that GLI2 binds to the IL-6Ralpha promoter and regulates IL-6Ralpha promoter activity as well as the expression of this receptor. In addition, we were able to rescue the reduction in IgM secretion in the GLI2 knockdown group by overexpressing IL-6Ralpha, thus defining the functional significance of this receptor in GLI2-mediated regulation of IgM secretion. Interestingly, this occurred independent of hedgehog (HH) signaling, a known regulator of GLI2, as manipulation of HH had no effect on IgM secretion or GLI activity. Given the poor prognosis associated with elevated IgM in WM patients, components of this new signaling axis could be important therapeutic targets.
Jackson, David A., "Modulation of the il-6 receptor alpha underlies GLI2-mediated regulation of immunoglobulin secretion in waldenstrom macroglobulinemia" (2015). Graduate Research Theses & Dissertations. 4011.
Northern Illinois University
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