Author(s):
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Winde, C.M. de; Veenbergen, S.; Young, K.H.; Xu-Monette, Z.Y.; Wang, X.X.; Xia, Y.; Jabbar, K.J.; Brand, M. van den; Schaaf, A. van der; Elfrink, S.; Houdt, I.S. van; Gijbels, M.J.;
Loo, F.A. van de
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Bennink, M.B.
;
Hebeda, K.M.
;
Groenen, P.J.
;
Krieken, J.H. van
;
Figdor, C.G.
;
Spriel, A.B. van
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Subject:
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Radboudumc 2: Cancer development and immune defence RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 5: Inflammatory diseases RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 9: Rare cancers RIMLS: Radboud Institute for Molecular Life Sciences |
Organization:
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Tumorimmunology Pathology Rheumatology |
Journal title:
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Journal of Clinical Investigation
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Abstract:
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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.
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