TY - JOUR
T1 - Tetraspanin CD37 protects against the development of B cell lymphoma
AU - de Winde, Charlotte M.
AU - Veenbergen, Sharon
AU - Young, Ken H.
AU - Xu-Monette, Zijun Y.
AU - Wang, Xiao-xiao
AU - Xia, Yi
AU - Jabbar, Kausat J.
AU - van den Brand, Michiel
AU - van der Schaaf, Alie
AU - Elfrink, Suraya
AU - van Houdt, Inge S.
AU - Gijbels, Marion J.
AU - van de Loo, Fons A. J.
AU - Bennink, Miranda B.
AU - Hebeda, Konnie M.
AU - Groenen, Patricia J. T. A.
AU - van Krieken, J. Han
AU - Figdor, Carl G.
AU - van Spriel, Annemiek B.
PY - 2016/2
Y1 - 2016/2
N2 - 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 116 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.
AB - 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 116 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.
U2 - 10.1172/JCI81041
DO - 10.1172/JCI81041
M3 - Article
C2 - 26784544
SN - 0021-9738
VL - 126
SP - 653
EP - 666
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -