Temporal and Spatial Control of V(D)J Recombination

V(D)J 重组的时空控制

• 批准号: 8293566
• 负责人: STEPHEN V DESIDERIO
• 金额: $ 33.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293566
• 关键词: Ablation; Adoptive Transfer; Affect; Age; Antigen Receptors; Automobile Driving; Binding; Biological Assay; Cell Cycle; Cells; Child; Childhood; Childhood Leukemia; Chromatin; Chromosomal Rearrangement; Chromosomal translocation; Chromosome abnormality; Complex; Copy Number Polymorphism; DNA; DNA Sequence Rearrangement; Defect; Development; Diagnosis; Disease; Environmental Risk Factor; Epigenetic Process; Event; Exhibits; Frequencies; Gene Rearrangement; Gene-Modified; Genes; Genetic; Genetic Recombination; Genetic Transcription; Genome; Genomic Instability; Genomics; Histone H3; Human; In Vitro; Knockout Mice; Laboratories; Lead; Lesion; Life; Light; Link; Loss of Heterozygosity; Lymphoid; Lymphoid Cell; Lymphomagenesis; Lysine; Maintenance; Malignant Neoplasms; Mammalian Cell; Mediating; Methods; Modeling; Modification; Molecular; Mus; Mutation; Oncogenic; Phase; Phenotype; Plants; Post-Translational Regulation; Proteins; Receptor Gene; SKP Cullin F-Box Protein Ligases; Site; Somatic Mutation; Stem cells; Testing; Time; Transcriptional Activation; Translocation Breakpoint; V(D)J Recombination; VDJ Recombinases; Work; homeodomain; homologous recombination; in vivo; leukemia; lymphoid neoplasm; mouse model; novel; progenitor; programs; recombinase; repaired; research study; tool; tumor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): A child has a 1 in 2000 chance of developing leukemia by the age of 15. The most common types of childhood leukemia typically exhibit gross chromosomal abnormalities. While the consequences of some of these abnormalities are understood, much less is known about how these genomic derangements occur in the first place, or how environmental factors affect the frequency of their occurrence. Tumor-associated chromosomal aberrations result from destabilizing DNA transactions, including V(D)J recombination, a form of programmed DNA rearrangement that normally serves to assemble antigen receptor genes. In preliminary work we have defined molecular mechanisms that constrain V(D)J recombination in time and in space, and have proceeded to demonstrate that mistimed recombination is associated with genomic instability and lymphomagenesis. Building on these accomplishments, the work proposed under this proposal aims to develop a mechanistic understanding of genomic instability in leukemic progenitors, to build new tools to uncover functional interactions between gross chromosomal abnormalities and cooperating mutations, and to define epigenetic mechanisms that may protect the genome by limiting the destabilizing effects of V(D)J recombinase activity. Under the first aim we will elucidate mechanisms by which posttranslational regulation of recombinase activity enforces genomic integrity in developing lymphoid cells. This aim is of particular importance because it is expected to shed light on mechanisms that initiate chromosomal rearrangements in leukemias and other malignancies. Under the second aim we will exploit the genomic plasticity associated with unscheduled V(D)J recombination to identify lymphomagenic interactions between chromosomal translocations and smaller genetic lesions. The third aim will define a specific mechanism by which the transcriptional activation of chromatin constrains V(D)J recombination to particular sites during normal and abnormal development. Thus the overarching themes of this proposal are to elucidate mechanisms that control genomic plasticity in developing lymphoid cells and to determine the relationships between these controls and intrinsic defenses against lymphoid cancer. PUBLIC HEALTH RELEVANCE: Cancers of lymphoid cells are among the most common life-threatening diseases of childhood. Abnormal rearrangements of chromosomal DNA contribute to the development of most of these cancers. Work under this project will help provide a framework for understanding how these abnormal rearrangements occur and may ultimately lead to novel methods for prediction, diagnosis and treatment.

描述（由申请人提供）：儿童在 15 岁时患白血病的几率为 2000 分之一。最常见的儿童白血病类型通常表现出严重的染色体异常。虽然人们了解其中一些异常的后果，但对于这些基因组紊乱最初是如何发生的，或者环境因素如何影响其发生频率，人们知之甚少。与肿瘤相关的染色体畸变是由不稳定的 DNA 交易引起的，包括 V(D)J 重组，这是一种程序化 DNA 重排形式，通常用于组装抗原受体基因。在初步工作中，我们已经定义了在时间和空间上限制 V(D)J 重组的分子机制，并进一步证明了不合时宜的重组与基因组不稳定性和淋巴瘤发生有关。在这些成就的基础上，本提案提出的工作旨在对白血病祖细胞的基因组不稳定性有一个机制上的理解，建立新的工具来揭示总染色体异常和协同突变之间的功能相互作用，并定义表观遗传机制，通过限制 V(D)J 重组酶活性的不稳定效应来保护基因组。在第一个目标下，我们将阐明重组酶活性的翻译后调节在发育中的淋巴细胞中增强基因组完整性的机制。这个目标特别重要，因为它是预期的 阐明在白血病和其他恶性肿瘤中启动染色体重排的机制。在第二个目标下，我们将利用与计划外 V(D)J 重组相关的基因组可塑性来识别染色体易位和较小遗传病变之间的淋巴瘤发生相互作用。第三个目标将定义一种特定机制，在正常和异常发育过程中，染色质的转录激活可将 V(D)J 重组限制在特定位点。因此，该提案的首要主题是阐明控制发育中淋巴细胞的基因组可塑性的机制，并确定这些控制与针对淋巴癌的内在防御之间的关系。 公共卫生相关性：淋巴细胞癌症是儿童期最常见的危及生命的疾病之一。染色体 DNA 的异常重排导致了大多数此类癌症的发生。该项目的工作将有助于提供一个框架来理解这些异常重排是如何发生的，并可能最终带来预测、诊断和治疗的新方法。