B cell non-Hodgkin lymphoma is the most prevalent hematological disease worldwide. Enhanced, autocrine IL-6 signaling has been observed in B lymphoma cells from patients, and therapeutic approaches targeting the IL-6 pathway are currently under investigation. However, the molecular events that cause the altered IL-6 signaling are still unknown. Charlotte de Winde, Sharon Veenbergen, and colleagues at Radboud University Medical Center report that CD37 plays a critical role in regulating IL-6 signaling in B lymphoma cells. Using CD37-deficient mice, the group demonstrated that loss of CD37 expression results in spontaneous, multiple-organ lymphoma that consists of IgA+, germinal center-like B cells. Adoptive transfer of CD37-deficient lymphoma cells to CD37-deficient or lymphocyte-deficient recipient mice induced new tumors with metastatic potential. Moreover, loss of CD37 expression corresponded with enhanced IL-6 signaling in B lymphoma cells, as evidenced by increased phosphorylation of the downstream mediators AKT and STAT3 and increased IL-6 production. Mice deficient in both CD37 and IL-6 were protected from lymphoma, further confirming that CD37 regulates the IL-6 signaling that facilitates disease development. The authors determined that CD37 deficiency promotes IL-6 signaling due to loss of CD37 binding to SOCS3, which inhibits SOCS3-mediated suppression of the IL-6 pathway. Evaluation of diseased tissue from patients with diffuse large B cell lymphoma revealed that IL-6 expression is enhanced in tumors that lack CD37 expression, and patients with CD37-deficent tumors exhibited worse overall survival than patients with CD37-expressing tumors. These findings indicate a molecular mechanism that controls tumor-promoting IL-6 signaling in spontaneous B cell lymphoma. The accompanying image shows immunohistochemistry staining of CD37 (red) in human lymphoma tissue (cell nuclei counterstained with hematoxylin in blue). The 4 panels correspond to tissue from 4 diffuse large B cell lymphoma patients. Note that tumors either exhibited ubiquitous CD37 expression (2 upper panels) or lacked CD37 expression (2 lower panels).
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
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