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

c-Myc 启动的转录因子级联对正常和致病性 B 细胞增殖的调节

• 批准号: 9457045
• 负责人: Takeshi Egawa
• 金额: $ 47.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9457045
• 关键词: Activated Lymphocyte; Adaptive Immune System; Affect; Affinity; Alpha Cell; Amplifiers; Antibodies; Antibody Response; Antigen Receptors; Antigen Targeting; Antigens; B Cell Proliferation; B lymphoid malignancy; B-Cell Leukemia; B-Cell Neoplasm; B-Lymphocytes; Biogenesis; Bone Marrow; CD4 Positive T Lymphocytes; Cancer Model; Cancerous; Cell Communication; Cell Death; Cell Proliferation; Cell division; Cells; Chronic; Clonal Expansion; DNA Damage; Darkness; Data; Development; Ephrin-A5; Equilibrium; Gatekeeping; Gene Targeting; Genes; Genetic; Genome; Genomics; Grant; Hand; Human; Immune response; Immune system; Immunity; Immunoglobulin Somatic Hypermutation; Incidence; Intuition; Knowledge; Laboratories; Lead; Light; Link; Lymphocyte; Lymphomagenesis; Maintenance; Malignant Neoplasms; Mature Lymphocyte; Mediating; Metabolic; Modeling; Mus; Mutagenesis; Oncogenic; Outcome; Pathogenicity; Pathway interactions; Population; Process; Proliferating; Publishing; Reaction; Regulation; Regulator Genes; Regulatory Pathway; Reporter; Role; Secondary to; Signal Transduction; Somatic Mutation; Source; Structure of germinal center of lymph node; T-Lymphocyte; TNFRSF5 gene; Testing; Transgenic Mice; Tumor Suppression; Tumor Suppressor Proteins; V(D)J Recombination; Validation; Variant; Virus Diseases; activation-induced cytidine deaminase; adaptive immune response; adaptive immunity; base; c-myc Genes; cell transformation; cytokine; experimental study; improved; in vivo; innovation; leukemia/lymphoma; loss of function; lymphocyte proliferation; lymphoid neoplasm; novel; oncogenic lymphocyte transformation; prevent; programs; response; risk minimization; transcription factor; tumor; tumorigenesis

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.

概括 淋巴细胞在发育和免疫反应过程中的克隆扩增是淋巴细胞的一个标志性特征 适应性免疫。转录因子 c-MYC 对于建立代谢激活状态至关重要 激活淋巴细胞并使其进入快速分裂周期。 c-MYC驱动的克隆 通过定量扩增功能性淋巴细胞群，扩增有利于宿主保护。乙 淋巴细胞还通过 MYC 依赖性增殖爆发来定性改善抗体反应 生发中心。因此，虽然 c-MYC 对于保护性免疫非常重要，但其异常表达也影响了 与人类和小鼠的许多癌症有关。事实上，GC 中表达 MYC 的增殖 B 细胞 及其在骨髓中的前体细胞是人类 B 细胞恶性肿瘤的主要来源，这可能 由于 RAG 蛋白和 AID 活性继发的基因组损伤同时存在而恶化 不仅针对抗原受体位点，还针对许多隐藏目标。那么，GC B细胞或B细胞如何 前体在面临 MYC 驱动的克隆扩张的需要的同时最大限度地降低有害结果的风险？ 我们最近发现，增殖的淋巴细胞在其克隆过程中暂时限制了 c-MYC 的表达。 扩张。在 GC 中，B 细胞仅使用 c-MYC 来启动增殖程序并利用其 下游因子AP4继续分裂。这种 c-MYC-AP4 转录因子传递是 产生针对慢性病毒感染的保护性抗体所必需的 GC 反应。自从 这种级联允许 GC B 细胞在空间和时间上分离亮区中的 c-MYC 表达， 暗区的AID活性，该机制可能间接或被动地有助于保护GC B细胞 与 c-MYC 相比，AP4 的致癌性较低。出乎意料的是，我们得到了初步结果表明 AP4 在一组完全独立的模型中充当 MYC 驱动的 B 细胞白血病的肿瘤抑制因子 实验。这些结果表明 MYC-AP4 轴对于支持必要的 B 细胞增殖至关重要 提供保护性免疫，同时保护增殖的 B 细胞免遭致癌转化。这 可能凸显了 MYC 诱导的基因调控途径的一种新颖的、违反直觉的功能，该途径充当 肿瘤抑制剂。在这笔资助中，我们将研究 T 独立于 MYC 维持 AP4 的机制 细胞帮助信号，这是正常 B 细胞和 AP4 介导的 B 细胞持久增殖所必需的 肿瘤抑制。