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.

总结 淋巴细胞在发育和免疫应答过程中的克隆扩增是淋巴细胞增殖的标志性特征。 适应性免疫转录因子c-MYC是建立代谢活化状态所必需的， 激活淋巴细胞，使它们进入快速分裂周期。c-MYC驱动的克隆 扩增通过定量扩增功能性淋巴细胞群体而有利于宿主保护。B 淋巴细胞还通过MYC依赖性增殖爆发定性地改善抗体应答， 老年中心。虽然c-MYC因此对于保护性免疫非常重要，但其异常表达也导致了免疫缺陷。 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 骨髓中的前体细胞是人类B细胞恶性肿瘤的主要来源， 继发于RAG蛋白和AID活性的基因组损伤的同时存在使其恶化 不仅靶向抗原受体位点，而且靶向许多隐蔽的靶点。那么，GC B细胞或B细胞 前体最大限度地减少有害结果的风险，同时面临MYC驱动的克隆扩张的需要？ 我们最近发现，增殖淋巴细胞在其克隆形成过程中暂时限制c-MYC的表达， 扩张.在GC中，B细胞使用c-MYC仅用于增殖程序的启动，并利用其 下游因素AP 4继续他们的分裂。这种c-MYC-AP 4转录因子传递是必需的， 产生针对慢性病毒感染的保护性抗体所必需的GC反应。以来 这种级联反应允许GC B细胞在空间上和时间上分离亮区中的c-MYC表达， AID在暗区的活性，这一机制可能间接或被动地有助于保护GC B细胞 如果AP 4与c-MYC相比致癌性较低。出乎意料的是，我们获得的初步结果表明， AP 4在一组完全独立的白血病细胞中作为肿瘤抑制因子MYC驱动的B细胞白血病发挥作用。 实验这些结果表明MYC-AP 4轴对于支持必需的B细胞增殖是必需的 用于保护性免疫，同时保护增殖的B细胞免于致癌转化。这 可能突出了MYC诱导的基因调控途径的一种新的、违反直觉的功能， 肿瘤抑制因子在这项资助中，我们将研究T细胞对AP 4的MYC非依赖性维持机制， 细胞辅助信号，这是正常B细胞和AP 4介导的 肿瘤抑制