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 3

Clonality of Cd37–/– B cell lymphomas and adoptive transfer to young mice.

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Clonality of Cd37–/– B cell lymphomas and adoptive transfer to young mic...
(A) DNA was extracted from mLNs of 18-month-old WT and Cd37–/– mice. VJ joinings from immunoglobulin heavy chain genes were amplified by the BIOMED-2 multiplex PCRs for IGH-VJ rearrangements, showing FR2 (FR1 and FR3 are shown in Supplemental Figure 4). Experiments were performed 2 times with 3 mice of each genotype. Data are shown for two lymphomas and one WT control tissue as well as human polyclonal and monoclonal control samples. (B) Lymphoma cells (5 × 106 cells) were injected subcutaneously in the flanks of 6- to 8-week-old Cd37–/– mice (n = 12), and tumor growth was measured in time. Each line represents an individual mouse. When tumors reached >2 cm2 in size, mice were sacrificed and lymphoid tissues were analyzed macroscopically by flow cytometry, histology, and immunohistochemistry (Supplemental Figure 5). (C) Lymphoma cells (5 × 106 cells) were injected subcutaneously in the flanks of 6- to 8-week-old Cd37–/– mice or immunocompromised nude mice (n = 6 mice per group), and tumor growth was measured in time. Data represent mean ± SEM. (D and E) Lymphoma cells (5 × 106 cells) were injected intravenously in the tail veins of 6- to 8-week-old immunocompromised NSG mice (n = 6). These mice lack the lymphocyte compartment, including CD19+B220+ B cells. Mice were sacrificed after 11 days, and (D) mLNs and (E) spleens were analyzed for presence of CD19+B220+ B cells by flow cytometry (left). In the right panel, each dot represents the percentage of CD19+B220+ B cells in the (D) mLN or (E) spleen per mouse. Data represent mean ± SEM.