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: 10229421
• 负责人: Takeshi Egawa
• 金额: $ 46.24万
• 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 2023-08-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229421
• 关键词: Activated Lymphocyte; Adaptive Immune System; Affect; Affinity; 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; Data; Development; Emu species; Ephrin-A5; Equilibrium; Exposure to; Gatekeeping; 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; antigen-specific T cells; 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 发育过程中淋巴细胞的克隆扩张和免疫反应是标志性的特征 自适应免疫。转录因子C-MYC对于建立代谢激活状态至关重要 活化的淋巴细胞，使它们能够进行快速分裂周期。 C-MYC驱动的克隆 扩展通过定量扩增功能性淋巴细胞种群来保护宿主保护。 b 淋巴细胞还通过依赖MYC依赖性增殖爆发来定性地改善抗体反应 生发中心。因此，C-MYC对于保护性免疫非常重要，但它的异常表达也具有 与人类和小鼠中的许多癌症有关。实际上，MYC表达GC中的增殖B细胞 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 由于抹布蛋白的活性和AID的同时存在基因组侮辱而变得恶化 这不仅靶向抗原受体基因座，而且还针对许多神秘靶标。然后，GC B细胞或B细胞如何 在面对MYC驱动的克隆扩张的需求的同时，前体降低了有害结果的风险？ 我们最近发现，增殖的淋巴细胞在其克隆期间时间限制C-MYC的表达 扩张。在GC中，B单元仅使用C-MYC来启动增殖程序，并利用其 下游因子AP4继续其分裂。此C-MYC-AP4转录因子需要交接 对针对慢性病毒感染的保护性抗体开发的必要GC反应。自从 该级联允许GC B细胞在光区中的空间和时间分离C-MYC的表达，并且 在黑暗区域的辅助活动，该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，我们获得了指示的初步结果 该AP4在完全独立的一组中充当肿瘤抑制MYC驱动的B细胞白血病 实验。这些结果表明，MYC-AP4轴对支持必要的B细胞增殖至关重要 为了保护性免疫和同时保护增殖的B细胞免受致癌转化的影响。这 可能会突出显示MYC诱导的基因调节途径的新颖的，违反直觉的功能，该途径起作用 肿瘤抑制剂。在这笔赠款中，我们将研究t 细胞帮助信号，这对于正常B细胞​​的持久增殖是必需的 肿瘤抑制。