Our long-term goal is to define the underlying mechanisms by which a surfeit of MYC expression in the context of auto-reactive B-cells is able to break immune tolerance. We have observed that mice that would otherwise be tolerant to a transgenic auto-antigen mounted an immune response to the antigen if MYC was vigorously expressed in the B-cell lineage. These findings demonstrate a critical role for MYC in the response of B-cells to antigen and expand the potential contributions of MYC to the genesis of lymphomas. The models we have developed should prove valuable for the further study of the mechanisms of lymphomagenesis, and for preclinical testing of new therapeutics. We propose to test the hypothesis that MYC is both a necessary and sufficient effector for the T helper-cell derived signals that regulate B- cell function in normal immune responses and in the genesis of lymphomas upon overexpression. This is an appealing hypothesis, since the same signaling mediators that are likely to be involved in the MYC-dependent regulation of B-cell tolerance and homeostasis are at play in the oncogenic functions of MYC, and may prove to be attractive therapeutic targets for lymphoproliferative diseases and lymphoid neoplasia. Specifically, we will: 1. Determine the necessity and sufficiency of MYC in the transduction of signals that arise from T-helper cells during the activation of naive B-cells and the subsequent homeostatic regulation of activated B-lymphocytes. 2. Examine the requirement of helper T-cells for the development and maintenance of antigen-dependent, MFC-driven, B-cell lymphomas. 3. Examine whether the reconstitution of CD4+ T cells that are usually lost in HIV patients may help prevent the initiation or affect the maintenance of MFC-driven, antigen dependent lymphomas. By defining the roles of MYC in lymphoid tolerance and homeostasis, we hope to aid in the discovery of new therapies to treat lymphoproliferative diseases and lymphoid malignancies. In addition, the details surrounding the mechanisms by which MYC affects lymphoid tolerance and homeostasis may provide further insights into the role of MYC in lymphoid neoplasia.
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