The Role of Tetraspanin CD37 in B-Cell Malignancy

Members of the tetraspanin superfamily of transmembrane proteins have roles in a variety of processes including cellular adhesion, migration, activation, proliferation, survival, and solid tumor metastasis. Although numerous tetraspanin proteins are expressed by immune cells, only a few have expression that is restricted to these cells. CD37 is not found in non-hematologic tissues and is highly expressed by mature B-cells, with greater than 15 times higher expression compared to other immune cells (Deckert et al., 2013). Recently there has been significant interest in CD37 as a therapeutic target in non-Hodgkin lymphoma and Chronic Lymphocytic Leukemia (CLL), as evidenced by the ongoing clinical development of four different anti-CD37 therapies. However, very little is known about the biological function of this protein. Ligation by the CD37-targeting peptide otlertuzumab leads to induction of both pro-survival Akt activation and pro-apoptotic SHP1 signaling, although cellular death is heavily favored (Lapalombella et al., 2012). Furthermore, CD37 is critical to normal plasma cell development, clustering VLA-4 (α4β1 integrin) on the surface of germinal center B-cells to allow integrin-mediated activation of Akt (van Spriel et al., 2012). In CLL, expression of the VLA-4 subunit CD49d is associated with more aggressive disease and promotes homing and adhesion to supportive cells within lymphoid tissues. This prompted us to explore the role of CD37 expression in B-cell malignancy using a CD37-deficient Eľ-TCL1 mouse model of CLL. For these studies, we monitored mice that were CD37 wild type, heterozygous knockout, or homozygous knockout (all hemizygous for the TCL1 transgene). While no significant difference was observed in the time until appearance of leukemia in peripheral blood, loss of CD37 led to decreased survival of TCL1 mice (p=0.032). In the same timeframe, non-TCL1 mice with CD37 deficiency did not exhibit impaired survival. While CD37 is predominantly seen in B-cells, the protein serves a role in other immune cells despite substantially lower expression. Our results are consistent with the recent reports on impaired dendritic cell migration in CD37 deficient mice, which is associated with decreased anti-tumor immunity in the context of a subcutaneously injected mouse cell line expressing a foreign human antigen (Gartlan et al., 2013). Our data support a potential role for CD37 in anti-tumor immune response against the syngeneic leukemia that arises spontaneously in the TCL1 model of CLL. Given the complex nature of this global knockout model, other functions of CD37 may be obscured. Ongoing studies will examine engraftment of CD37-deficient or wildtype TCL1 leukemia into healthy mice to elucidate whether the B-cell intrinsic role of CD37 is supportive of the leukemia, independent of an extrinsic role in anti-tumor immunity.