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 6

CD37 controls the IL-6 pathway via SOCS3, and lymphoma development is dependent on IL-6 in vivo.

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CD37 controls the IL-6 pathway via SOCS3, and lymphoma development is de...
(A) Comparable surface expression of IL-6Rα and gp130 in the plasma membrane of B220+IgA+ B cells from 18-month-old WT and Cd37–/– mice analyzed by flow cytometry (specific antibody staining [black] versus isotype control antibody [gray]). MFI, mean fluorescence intensity. (B) Protein levels of SOCS3 in mLN cells from 18-month-old WT and Cd37–/– mice, as detected by Western blot (noncontiguous lanes from the same gel). SOCS3 protein levels were normalized to actin levels (n = 5 mice per genotype). Data represent mean ± SEM. (C) HEK293 cells were cotransfected (TF) with CD37-GFP (or GFP alone) and SOCS3, followed by immunoprecipitation with anti-GFP or isotype control IgG. Western blots were probed with anti-SOCS3 (26 kDa) and anti-GFP (CD37-GFP, 60–75 kDa, due to heavy glycosylation, ref. 66; noncontiguous lanes from the same gel). (D) Colocalization of CD37 (red) and SOCS3 (green) or control antibody was studied on human JY B cells without (–) or with (+) IL-6 stimulation by confocal microscopy. Colocalization is shown in yellow (white arrows). Manders coefficient was determined with n ≥ 17 cells from 3 independent experiments (each dot represents a single cell). Data represent mean ± SEM. *P < 0.05, Mann-Whitney nonparametric test. (E) Colocalization of CD37 (red) and IL-6Rα (green) or control antibody was studied on human JY B cells by confocal microscopy. Colocalization (yellow) was independent of IL-6 stimulation. Data are shown for B cells without IL-6 stimulation. (F) p-STAT3 (76–78 kDa) levels in NALM-6 cells, which were mock transfected or transfected with CD37-GFP, with or without IL-6 stimulation for 60 minutes. Actin (42 kDa) was used as loading control (noncontiguous lanes from the same gel). (G) Cd37–/–xIl6–/– mice are protected against development of B cell lymphoma (n = 26) (see Supplemental Table 1 for details). Original magnification: ×630 (D and E); ×1,260 (insets, D and E).