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细胞背景下过量表达MYC能够打破免疫耐受的潜在机制。我们观察到，如果MYC在B细胞系中强烈表达，那么原本对转基因自身抗原具有耐受性的小鼠就会对该抗原产生免疫反应。这些发现表明MYC在B细胞对抗原的反应中起着关键作用，并扩大了MYC在淋巴瘤发生中的潜在贡献。我们开发的模型应该被证明对进一步研究淋巴肿大的机制和临床前新疗法的测试是有价值的。我们建议检验这一假设，即MYC既是T辅助细胞来源的信号的必要和充分的效应器，在正常免疫反应中调节B细胞的功能，也在过表达时调节淋巴瘤的发生。这是一个吸引人的假说，因为可能参与依赖MYC调节B细胞耐受性和动态平衡的相同信号介质在MYC的致癌功能中发挥作用，并可能被证明是淋巴增生性疾病和淋巴样肿瘤的有吸引力的治疗靶点。具体地说，我们将：1.确定MYC在幼稚B细胞激活期间T辅助细胞产生的信号的转导以及随后激活的B淋巴细胞的动态平衡调节中的必要性和充分性。2.研究辅助T细胞在抗原依赖、MFC驱动的B细胞淋巴瘤的发生和维持中的需求。3.检查HIV患者中通常丢失的CD4+T细胞的重建是否有助于防止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在淋巴耐受和动态平衡中的作用，我们希望有助于发现治疗淋巴增生性疾病和淋巴系统恶性肿瘤的新疗法。此外，围绕MYC影响淋巴耐受和动态平衡的机制的细节可能为进一步了解MYC在淋巴肿瘤中的作用提供帮助。

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.