Modulation of the IL-6 receptor a underlies GLI2-mediated regulation of Ig secretion in Waldenström macroglobulinemia cells

David A. Jackson, Timothy D. Smith, Nansalmaa Amarsaikhan, Weiguo Han, Matthew S. Neil, Shannon K. Boi, Anne M. Vrabel, Ezequiel J. Tolosa, Luciana L. Almada, Martin E Fernandez-Zapico, Sherine F. Elsawa

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2908-2916
Number of pages9
JournalJournal of Immunology
Volume195
Issue number6
DOIs
StatePublished - Sep 15 2015

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Interleukin-6 Receptors
Waldenstrom Macroglobulinemia
Immunoglobulin M
B-Lymphocytes
Chromatin Immunoprecipitation
Luciferases
Transcription Factors
Pharmacology
Morbidity
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

Jackson, D. A., Smith, T. D., Amarsaikhan, N., Han, W., Neil, M. S., Boi, S. K., ... Elsawa, S. F. (2015). Modulation of the IL-6 receptor a underlies GLI2-mediated regulation of Ig secretion in Waldenström macroglobulinemia cells. Journal of Immunology, 195(6), 2908-2916. https://doi.org/10.4049/jimmunol.1402974

Modulation of the IL-6 receptor a underlies GLI2-mediated regulation of Ig secretion in Waldenström macroglobulinemia cells. / Jackson, David A.; Smith, Timothy D.; Amarsaikhan, Nansalmaa; Han, Weiguo; Neil, Matthew S.; Boi, Shannon K.; Vrabel, Anne M.; Tolosa, Ezequiel J.; Almada, Luciana L.; Fernandez-Zapico, Martin E; Elsawa, Sherine F.

In: Journal of Immunology, Vol. 195, No. 6, 15.09.2015, p. 2908-2916.

Research output: Contribution to journalArticle

Jackson, DA, Smith, TD, Amarsaikhan, N, Han, W, Neil, MS, Boi, SK, Vrabel, AM, Tolosa, EJ, Almada, LL, Fernandez-Zapico, ME & Elsawa, SF 2015, 'Modulation of the IL-6 receptor a underlies GLI2-mediated regulation of Ig secretion in Waldenström macroglobulinemia cells', Journal of Immunology, vol. 195, no. 6, pp. 2908-2916. https://doi.org/10.4049/jimmunol.1402974
Jackson, David A. ; Smith, Timothy D. ; Amarsaikhan, Nansalmaa ; Han, Weiguo ; Neil, Matthew S. ; Boi, Shannon K. ; Vrabel, Anne M. ; Tolosa, Ezequiel J. ; Almada, Luciana L. ; Fernandez-Zapico, Martin E ; Elsawa, Sherine F. / Modulation of the IL-6 receptor a underlies GLI2-mediated regulation of Ig secretion in Waldenström macroglobulinemia cells. In: Journal of Immunology. 2015 ; Vol. 195, No. 6. pp. 2908-2916.
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AU - Han, Weiguo

AU - Neil, Matthew S.

AU - Boi, Shannon K.

AU - Vrabel, Anne M.

AU - Tolosa, Ezequiel J.

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AU - Fernandez-Zapico, Martin E

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