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 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 2

Phenotypical characterization of the Cd37–/– B cell lymphomas.

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Phenotypical characterization of the Cd37–/– B cell lymphomas. (A) Flow ...
(A) Flow cytometry analyses of B cells of mLNs from 18-month-old WT and Cd37–/– mice. B cells were identified by gating on CD19+B220+ cells that were stained for CD86, MHC-II, PNA, CD138, CD43, and CD40 (thick black lines indicate Cd37–/–; thin black lines indicate WT; gray lines indicate isotype control). (B) Immunohistochemical analyses of mLNs from 18-month-old WT and Cd37–/– mice using GC-specific staining with PNA and GL7 antibody. Scale bar: 300 μm (first column); 50 μm (second column); 300 μm (third column); 50 μm (fourth column). Lines indicate the border of the B cell follicle. (C) Characterization of the B cell receptor (immunoglobulin) isotype on B cells from mLNs of 18-month-old WT and Cd37–/– mice. CD19+B220+ cells were stained for IgM, IgG, and IgA, followed by immunofluorescence (first 3 columns) and immunohistochemistry (fourth column). Scale bar: 70 μm. Experiments were performed 4 times with at least 4 mice of each genotype per group.