Tolerance to this self antigen is overcome by the over expression of c Myc in these cells and the result ing autoreactive B cells are hyperproliferative and form tumors in the lymph nodes and spleen. The lymphoma phenotype occurs in 100% of the EMyc/BCRHEL/HEL transgenic mice with a median latency of 8 weeks. The tumors can be transplanted into unmanipulated C57BL/6 mice and the transplant recipients uniformly develop tumors after 3 4 weeks that appear identical to those in the transgenic donors. This transgenic mouse line is similar to other lymphoma models that overexpress c Myc, except for context of overexpression, in auto reactive B cells. Antigen receptor activation may be simi larly involved in tumorigenesis in certain human lymphoid malignancies.

The development of the EMyc/BCRHEL/HEL mice per mits preclinical testing in this model in an effort to ascer tain whether clinical trials of FTIs on mature B cell lymphomas, such as Burkitts lymphoma, might be in order. In this report, we have demonstrated that FTIs can disrupt the growth and survival pathways in the murine tumor cells. Mice with transplanted tumors showed responses to either FTI, demonstrating effectiveness in vivo of this class of drug against this malignant B cell lym phoma. These preclinical results may have important implications for the treatment of B cell lymphomas in humans, particularly those whose proliferation or survival are dependent on antigen activation. Results Mouse B cell lymphoma cells are sensitive to L 744,832 in vitro In order to evaluate whether the murine mature B cell lymphoma might respond to FTIs, we measured prolifer ation of tumor cells in vitro.

The Brefeldin_A tumor B cells from EMyc/BCRHEL/HEL transgenic mice proliferated in the absence of exogenous stimulation. In contrast, na ve B cells from mice carrying only the BCRHEL transgene did not proliferate without stimulation, but showed several rounds of cell division when stimulated with a mixture of anti IgM and anti CD40. The growth of the murine tumor cells in culture provided the opportunity to test the effi cacy of experimental compounds such as FTIs. Proliferation of the mouse lymphoma cells can be blocked by the FTI, L 744,832. At relatively low concentra tions of this drug, there was no antiproliferative effect on either nontransformed or tumor B cells.

At 4 M L 744,832, a slight effect was seen on the nontransformed B cells, but the proliferation of the tumor cells was almost com pletely blocked. At a concentration of L 744,832 that was not likely to be pharmacologically rele vant, the proliferation of both cell types was almost completely blocked. From these data, we concluded that L 744,832 prevented the proliferation of the mouse lymphoma cells in vitro and that, under these conditions, it had a greater effect on the tumor cells than on the proliferation of activated, non transformed B cells stimulated by antigen receptor and CD40 activation.