Regulation of Normal and Pathogenic B Cell Proliferation by a c-Myc-initiated Transcription Factor Cascade

摘要 淋巴细胞在发育和免疫反应过程中的克隆性扩张是该病的一个特点 适应性免疫。转录因子c-myc是建立新陈代谢激活状态所必需的。 激活淋巴细胞，使其进入快速分裂周期。C-myc基因驱动的克隆 通过定量扩增功能淋巴细胞群，扩增有利于宿主保护。B类 淋巴细胞也可以通过依赖MYC的增殖爆发来定性地改善抗体反应。 生发中心。虽然c-myc因此对保护性免疫非常重要，但它的异常表达也 与人类和小鼠的许多癌症有关。事实上，在GC中表达MYC的增殖性B细胞 而它们在骨髓中的前体是人类B细胞恶性肿瘤的主要来源，这可能是 RAG蛋白和AID活性继发的基因组损伤的同时存在使病情恶化 这不仅是靶抗原受体基因座，也是一些隐蔽的靶点。那么，GC B细胞还是B细胞 前体将有害结果的风险降至最低，同时面临MYC驱动的克隆扩张的需求？ 我们最近发现，增殖的淋巴细胞在其克隆过程中会暂时限制c-myc的表达。 扩张。在GC中，B细胞仅使用c-myc启动增殖程序，并利用其 下游因素AP4继续他们的分歧。这种c-myc-ap4转录因子的传递是 发展针对慢性病毒感染的保护性抗体所必需的GC反应。自.以来 这一级联允许GC B细胞在空间和时间上分离光区的c-myc表达，并 在暗区的辅助活动，这一机制可能间接或被动地有助于保护GC B细胞 如果与c-myc相比，AP4的致癌性较低。出乎意料的是，我们已经获得了初步结果，表明 AP4在一组完全独立的 实验。这些结果表明，MYC-AP4轴对支持必要的B细胞增殖是必不可少的 用于保护性免疫，同时保护增殖的B细胞免受致癌转化。这 可能会突出MYC诱导的基因调控途径的一种新的、违反直觉的功能，它的功能是 肿瘤抑制因子。在这项资助中，我们将研究T对AP4的MYC非依赖性维持的机制 细胞帮助信号，这是正常B细胞和AP4介导的B细胞持续增殖所必需的 肿瘤抑制。

Summary Clonal expansion of lymphocytes during the development and immune responses is a hallmark feature of adaptive immunity. The transcription factor c-MYC is essential to establish metabolically activate states in activated lymphocytes and allow them to proceed into rapid division cycles. The c-MYC driven clonal expansion is beneficial for host protection by quantitatively amplifying functional lymphocyte populations. B lymphocytes also qualitatively improve antibody responses through MYC-dependent proliferative bursts in the Germinal centers. While c-MYC is thus very important for protective immunity, its aberrant expression has also been associated with many cancers in humans and mice. Indeed, MYC-expressing proliferating B cells in GCs and their precursors in the bone marrow are the major sources of B cell malignancies in humans, which might be worsened by the concurrent presence of genomic insults secondary to activities of RAG proteins and AID that not only target antigen receptor loci but also a number of cryptic targets. Then, how GC B cells or B cell precursors minimize the risk of deleterious outcomes while facing the need for MYC-driven clonal expansion? We have recently found that proliferating lymphocytes temporally restrict c-MYC expression during their clonal expansion. In the GCs, B cells use c-MYC only for the initiation of proliferative program and utilize its downstream factor AP4 to continue their divisions. This c-MYC-AP4 transcription factor hand-off is required for the requisite GC responses for the development of protective antibodies against chronic viral infection. Since this cascade allows GC B cells to spatially and temporally segregate c-MYC expression in the light zone and AID activity in the dark zone, this mechanism may indirectly or passively contribute to protection of GC B cells if AP4 is less oncogenic compared to c-MYC. Unexpectedly, we have obtained preliminary results indicating that AP4 functions as a tumor suppressor MYC-driven B cell leukemia in a completely independent set of experiments. These results suggest that the MYC-AP4 axis is essential to support requisite B cell proliferation for protective immunity and simultaneously protect proliferating B cells from oncogenic transformation. This may highlight a novel, counterintuitive function of a MYC-induced gene regulatory pathway that functions as a tumor suppressor. In this grant, we will study the mechanisms of MYC-independent maintenance of AP4 by T cell help signals, which is necessary for durable proliferation of normal B cells and those of AP4-mediated tumor suppression.