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 1

Spontaneous development of B cell lymphoma in Cd37–/– mice.

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Spontaneous development of B cell lymphoma in Cd37–/– mice. (A) Cd37–/– ...
(A) Cd37–/– mice demonstrate splenomegaly (0.09 ± 0.01 vs. 0.21 ± 0.04 g spleen weight in WT and Cd37–/– mice, respectively; n = 10, *P < 0.02, unpaired 2-tailed Student’s t test). Data represent mean ± SEM. (B) Cd37–/– mice develop large malignancies in mLNs upon aging. Macroscopic incidence of lymphomas in Cd37–/– mice (n = 48) versus that in age-matched WT littermates (n = 52). (C) Histological analyses of the mLNs from 18-month-old WT and Cd37–/– mice using H&E tissue stainings. Cd37–/– mLNs were diagnosed as mature B cell lymphomas. Scale bar: 300 μm (first column); 80 μm (second column); 40 μm (third column); 20 μm (fourth column). (D) Immunohistochemical analyses of mLNs from 18-month-old WT and Cd37–/– mice. Tissues were stained for B220, CD19, CD3, and CD68 using fast red and hematoxylin counterstaining (F4/80, Gr1, CD138, and isotype control stainings are presented in Supplemental Figure 1A). Note the disorganization of Cd37–/– mLN tissues that consist of small and large pleiomorphic B cells and presence of infiltrating T cells, histocytes, and macrophages. Black lines indicate the border between the B cell follicle and T cell area in WT tissues. Scale bar: 25 μm. Experiments were repeated 5 times with at least 4 mice of each genotype per group.