Tetraspanin CD37 protects against the development of B cell lymphoma
Charlotte M. de Winde, … , Carl G. Figdor, Annemiek B. van Spriel
Charlotte M. de Winde, … , Carl G. Figdor, Annemiek B. van Spriel
Published February 1, 2016; First published January 19, 2016
Citation Information: J Clin Invest. 2016;126(2):653-666. https://doi.org/10.1172/JCI81041.
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Research Article Oncology

Tetraspanin CD37 protects against the development of B cell lymphoma

Abstract

Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center–derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37– B cell malignancies as a possible therapeutic intervention.

Authors

Charlotte M. de Winde, Sharon Veenbergen, Ken H. Young, Zijun Y. Xu-Monette, Xiao-xiao Wang, Yi Xia, Kausar J. Jabbar, Michiel van den Brand, Alie van der Schaaf, Suraya Elfrink, Inge S. van Houdt, Marion J. Gijbels, Fons A.J. van de Loo, Miranda B. Bennink, Konnie M. Hebeda, Patricia J.T.A. Groenen, J. Han van Krieken, Carl G. Figdor, Annemiek B. van Spriel

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Figure 7

Loss of CD37 in lymphomas of patients with DLBCL correlates with upregulated IL-6 signaling.

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Loss of CD37 in lymphomas of patients with DLBCL correlates with upregul...
(A) CD37 immunohistochemistry staining (red) of GCB-DLBCL biopsies. Cell nuclei were counterstained with hematoxylin (blue). Representative stainings of 2 CD37+ and CD37– tumors are shown. Original magnification: ×100. (B) Expression of IL6 mRNA levels in lymphomas of 47 patients with GCB-DLBCL expressing (CD37+, n = 15; red dots) or not expressing (CD37–, n = 32; blue dots) cell surface CD37. Data represent mean ± SD. **P = 0.0098; unpaired Student’s t test. (C) Expression of IL-6 protein levels in sera of patients with DLBCL with CD37– tumors (n = 3). Cytokine levels of patients with DLBCL with CD37+ tumors were not detectable above background signal (ND) (n = 5). Data represent mean ± SEM. **P = 0.0084, Mann-Whitney nonparametric test was used for statistical analysis. (D) Expression of AKT1 mRNA in lymphomas of patients with GCB-DLBCL without CD37 expression (CD37–, n = 32, blue dots) compared with CD37+ tumors (n = 15, red dots). Data represent mean ± SD. *P = 0.0476, unpaired Student’s t test. (E) Nuclear expression of (activated) p-STAT3 protein in lymphomas of patients with GCB-DLBCL with CD37– tumors (n = 32, blue dots) compared with CD37+ tumors (n = 15, red dots). Data represent mean ± SD. P = 0.0915, unpaired Student’s t test.