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MYC表达过剩能够打破免疫耐受的潜在机制。我们观察到，如果MYC在b细胞谱系中大量表达，本可以耐受转基因自身抗原的小鼠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作用。我们所建立的模型对于淋巴瘤发生机制的进一步研究和新疗法的临床前测试都是有价值的。我们建议验证这样的假设，即MYC是T辅助细胞来源的信号的必要和充分的效应物，这些信号调节正常免疫反应中的B细胞功能，并在过度表达后发生淋巴瘤。这是一个很有吸引力的假设，因为同样的信号介质可能参与MYC依赖的b细胞耐受和稳态调节，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样瘤变的有吸引力的治疗靶点。具体来说，我们将：1。确定MYC在初始b细胞激活过程中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。通过确定MYC在淋巴细胞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细胞恶性肿瘤的新疗法。此外，MYC影响淋巴细胞耐受和体内平衡机制的细节可能为MYC在淋巴样瘤变中的作用提供进一步的见解。

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.