title: Modulation of the IL-6 Receptor α Underlies GLI2-Mediated Regulation of Ig Secretion in Waldenström Macroglobulinemia Cells.
abstract: Ig secretion by terminally differentiated B cells is an important component of the immune response to foreign pathogens. Its overproduction is a defining characteristic of several B cell malignancies, including Waldenström macroglobulinemia (WM), where elevated 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. In this study, we define a novel pathway involving the oncogenic transcription factor GLI2 modulating IgM secretion by WM malignant cells. Pharmacological and genetic inhibition of GLI2 in WM malignant cells resulted in a reduction in IgM secretion. Screening for a mechanism identified the IL-6Rα (gp80) subunit 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-6Rα promoter and regulates its activity as well as the expression of this receptor. Additionally, we were able to rescue the reduction in IgM secretion in the GLI2 knockdown group by overexpressing IL-6Rα, thus defining the functional significance of this receptor in GLI2-mediated regulation of IgM secretion. Interestingly, this occurred independent of Hedgehog signaling, a known regulator of GLI2, as manipulation of Hedgehog had no effect on IgM secretion. Given the poor prognosis associated with elevated IgM in WM patients, components of this new signaling axis could be important therapeutic targets.
authors.affiliation: Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115; and.
authors.forename: David A
authors.initials: DA
authors.lastname: Jackson
authors.affiliation: Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115; and.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Smith
authors.affiliation: Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115; and.
authors.forename: Nansalmaa
authors.initials: N
authors.lastname: Amarsaikhan
authors.affiliation: Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115; and.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115; and.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Neil
authors.affiliation: Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115; and.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Boi
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Vrabel
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905.
authors.forename: Ezequiel J
authors.initials: EJ
authors.lastname: Tolosa
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905.
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115; and selsawa@niu.edu.
authors.forename: Sherine F
authors.identifier: http://orcid.org/0000-0002-3917-3078
authors.initials: SF
authors.lastname: Elsawa
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology*; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000276:immunology; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D008258:Waldenstrom Macroglobulinemia / Q000378:metabolism / Q000473:pathology*; D000075746:Zinc Finger Protein Gli2
chemical_list: C476399:Cd44 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D018960:Hyaluronan Receptors; D007075:Immunoglobulin M; D051741:Kruppel-Like Transcription Factors; D019947:Receptors, Interleukin-6; D000075746:Zinc Finger Protein Gli2; C033027:secretory IgM