MYC-induced breach of B-cell anergy in AIDS-related NHLs

描述（由申请人提供）：我们的长期目标是确定在自身反应性B细胞的背景下MYC表达过量能够破坏免疫耐受的潜在机制。我们已经观察到，如果MYC在B细胞谱系中强烈表达，则原本对转基因自身抗原耐受的小鼠对抗原产生免疫应答。这些发现证明了MYC在B细胞对抗原的应答中的关键作用，并扩大了MYC对淋巴瘤发生的潜在贡献。我们开发的模型应该证明有价值的淋巴瘤发生的机制的进一步研究，并为新的治疗方法的临床前测试。我们建议测试的假设，即MYC是一个必要的和足够的效应T辅助细胞衍生的信号，调节B-细胞在正常的免疫反应中的功能，并在淋巴瘤的发生过度。这是一个有吸引力的假设，因为可能参与MYC依赖性调节B细胞耐受性和稳态的相同信号传导介质在MYC的致癌功能中起作用，并且可能被证明是淋巴增生性疾病和淋巴瘤形成的有吸引力的治疗靶点。具体来说，我们将：1。确定MYC在幼稚B细胞活化过程中从T辅助细胞产生的信号转导以及随后活化B淋巴细胞的稳态调节中的必要性和充分性。2.检查辅助T细胞对抗原依赖性、MFC驱动的B细胞淋巴瘤的发展和维持的需求。3.检查HIV患者通常丢失的CD 4 + T细胞的重建是否有助于预防MFC驱动的抗原依赖性淋巴瘤的发生或影响其维持。通过明确MYC在淋巴耐受和体内平衡中的作用，我们希望有助于发现治疗淋巴增生性疾病和淋巴恶性肿瘤的新疗法。此外，围绕MYC影响淋巴耐受和稳态的机制的细节可能会进一步了解MYC在淋巴瘤形成中的作用。

DESCRIPTION (provided by applicant): 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.