FTY720 is an immunosuppressant developed to prevent organ transplant rejection. Recent studies indicate an additional role for FTY720 in inducing cell apoptosis. We demonstrate here that FTY720 mediates toxic effects in cell lines representing different B-cell malignancies and primary B cells from patients with chronic lymphocytic leukemia (CLL). In contrast to previous reports in T-cell lines, FTY720-induced toxicity in the Raji cell line and primary CLL B cells is independent of activation of caspases or poly(ADP-ribose) polymerase processing. Further, pancaspase inhibitor Z-VAD-fmk failed to rescue these cells from apoptosis mediated by FTY720. FTY720 induced down-regulation of Mcl-1 but not Bcl-2 in CLL B cells. Overexpression of Bcl-2 failed to protect transformed B cells from FTY720-induced apoptosis, suggesting a Bcl-2–independent mechanism. Interestingly, FTY720 induced protein phosphatase 2a (PP2a) activation and downstream dephosphorylation of ERK1/2, whereas okadaic acid at concentrations that inhibited the FTY720-induced PP2a activation also resulted in inhibition of FTY720-mediated apoptosis and restoration of baseline ERK1/2 phosphorylation in primary CLL cells, indicating a role for PP2a activation in FTY720-induced cytotoxicity. Further, FTY720 treatment resulted in significant prolonged survival in a xenograft severe combined immunodeficiency (SCID) mouse model of disseminated B-cell lymphoma/leukemia. These results provide the first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B-cell malignancies, including CLL.
CD37 is a lineage-specific B-cell antigen that to date has been neglected as an attractive therapeutic target. To exploit this, novel CD37-specific small modular immunopharmaceuticals ( IntroductionImmunotherapy using monoclonal antibodies (MAbs) is emerging as a safe and selective method for the treatment of cancer. 1 The role of monoclonal antibodies in B-cell malignancies has expanded since the introduction of rituximab (Rituxan) targeted against the CD20 antigen on the B-cell surface in 1997. Numerous studies have confirmed the efficacy of rituximab as a single agent and in combination therapy in low-grade non-Hodgkin lymphoma (NHL), 2-6 mantle-cell lymphoma, 7-11 diffuse large-cell lymphoma, 12,13 and Burkitt leukemia/lymphoma. 14 However, only a subset of patients respond to therapy and the majority of those eventually relapse after rituximab treatment. Therefore, identification of new therapeutic targets on B cells that are potentially more effective than CD20 represents a novel strategy for therapy of B-cell malignancies.The CD37 antigen is one potential target that has not been adequately evaluated. CD37 is a heavily glycosylated 40-to 52-kDa glycoprotein and a member of the tetraspan transmembrane family of proteins. 15,16 CD37 is expressed strongly on the surface of B cells and transformed mature B-cell leukemia and lymphoma cells [17][18][19][20]22,23,25,26 but is either absent or minimally expressed on normal T cells. 21 The CD37 antigen is expressed on monocytes and granulocytes at very low density and is absent on natural killer (NK) cells, platelets, and erythrocytes. 15,22 During B-cell development, CD37 is expressed in cells progressing from pre-B to peripheral mature B-cell stages and is absent on terminal differentiation to plasma cells. 23 Although the precise function of CD37 remains unknown, it has been found to form complexes with CD53, CD81, CD82, and class II glycoprotein on B-cell surface that may represent an ion channel or a transporter. 24 CD37 has modest internalization and shedding in transformed B cells expressing the antigen. 25,26 It is highly expressed in endosomes and exosomes in B lymphocytes, reflecting possible involvement in intracellular trafficking and antigen presentation. 15 Targeted inactivation of CD37 in mice revealed no changes in the development of lymphoid organs but a reduced IgG1 level in the sera and an alteration of response to T-cell-dependent antigens, indicating a possible role of CD37 in T cell-B cell interaction. 27 Given the relative B-cell selectivity, CD37 thus represents a valuable therapeutic target for malignancies derived from peripheral mature B cells, such as B-cell chronic lymphocytic leukemia (CLL), hairy-cell leukemia (HCL), and B-cell NHL. 25,26 In particular, CLL may be a good target of CD37-based immunotherapy, because the expression of CD37 is relatively high, even compared with CD20, in this type of leukemia. 17 Efforts to target CD37 clinically have been limited. One reported preclinical trial performed in the late 1980s examined the ...
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