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Prenatal adenovirus infection, inhibition of DNA repair, and childhood leukemia

产前腺病毒感染、DNA 修复抑制和儿童白血病

基本信息

批准号：
7807094
负责人：
David Arnold Ornelles
金额：
$ 43.11万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-20 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7807094
关键词：
Acute Acute Lymphocytic Leukemia Acute leukemia Adenovirus Infections Adenovirus Protein Adenoviruses Affect Archives Biology Blood Blood specimen CD34 gene Cell Line Cells Characteristics Child Childhood Childhood Leukemia Chromosome abnormality Chromosomes Clinical Comet Assay Cytopathology DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Inhibition DNA biosynthesis Development Disease Outcome Etiology Event Frequencies Genes Hematopoietic stem cells Human In Vitro Individual Infant Infection Laboratories Lead Lesion Leukemic Cell Leukocytes Ligation Lymphocyte Lymphoid Lymphoid Cell Malignant Neoplasms Measures Mediating Mitotic Recombination Molecular Molecular Cytogenetics Monitor Nature Neonatal Newborn Infant Nucleic Acids One-Step dentin bonding system Phosphorylation Phosphotransferases Production Proteins Pulsed-Field Gel Electrophoresis RUNX1 gene Running Signal Transduction Sister Chromatid Exchange Stem cells Testing Umbilical Cord Blood Viral Genes Virus Virus Diseases Work base cancer cell cohort fusion gene in utero leukemia leukemogenesis microorganism pathogen prenatal public health relevance repaired research study response stem tumorigenesis viral DNA

项目摘要

DESCRIPTION (provided by applicant): Acute leukemias, the most common malignancy of childhood, have long been suspected of having an infectious etiology. We hypothesize that the common species C adenoviruses are responsible for the initiating step in some acute childhood leukemias. This hypothesis is based on the observation that species C adenovirus DNA is more frequently found in the blood of newborn children that later develop acute lymphoblastic leukemia than in the blood of children that do not develop leukemia. Additional support derives from observations made in the Ornelles and Gooding laboratories indicating that adenovirus infection of a lymphoid progenitor cell could produce the expanded clones of translocation-bearing cells that are the starting point for leukemia development in children. Studies proposed in this application will test this hypothesis through the following specific aims: (1) To evaluate the coincidence between prenatal infection with species C adenovirus, the occurrence of leukemia-associated translocations, and the eventual development of leukemia using archived Guthrie cards and fresh cord blood. (2) To elucidate the impact of adenovirus on DNA-repair in lymphoid cells. (3) To determine the impact of adenovirus infection on the integrity of lymphocyte cell DNA. (4) To evaluate adenovirus replication and the cytopathology of adenovirus in leukemic cells and hematopoietic progenitor cells. The studies proposed in this application will test directly the possibility that species C adenovirus infection is one step in the sequence of events leading to childhood leukemia. In addition, this work will identify cellular genes that affect adenovirus replication in lymphoid cells and determine the frequency of prenatal infection with this virus. These studies may provide support for hit-and-run mechanisms, that have been postulated for several viruses, in human oncogenesis. PUBLIC HEALTH RELEVANCE: These experiments will determine if a common and relatively innocuous virus, adenovirus, has the potential to contribute to acute childhood leukemia. These studies will advance our understanding of many aspects of adenovirus biology including the little known replication cycle of this virus in white blood cells and the frequency of adenovirus infections in the newborn. This work could provide the basis for early testing as well as help develop a simple treatment for the most common cancer of children.

描述（由申请人提供）：急性白血病是儿童期最常见的恶性肿瘤，长期以来一直被怀疑具有感染性病因。我们推测，常见的C类腺病毒是负责在一些急性儿童白血病的起始步骤。这一假说是基于观察到C种腺病毒DNA更频繁地发现在新生儿的血液中，后来发展成急性淋巴细胞白血病比在儿童的血液中没有发展白血病。Ornelles和Gooding实验室的观察结果进一步支持了这一观点，即腺病毒感染淋巴祖细胞可产生易位携带细胞的扩增克隆，而这些细胞是儿童白血病发展的起点。本申请中提出的研究将通过以下具体目的来检验这一假设：（1）使用存档的古特里卡和新鲜脐带血来评估产前感染C种腺病毒、白血病相关易位的发生和白血病的最终发展之间的一致性。(2)阐明腺病毒对淋巴细胞DNA修复的影响。(3)确定腺病毒感染对淋巴细胞DNA完整性的影响。(4)目的探讨腺病毒在白血病细胞和造血祖细胞中的复制及细胞病理学特征。本申请中提出的研究将直接测试C种腺病毒感染是导致儿童白血病的事件序列中的一个步骤的可能性。此外，这项工作将确定影响腺病毒在淋巴细胞中复制的细胞基因，并确定产前感染这种病毒的频率。这些研究可能提供支持的打了就跑的机制，已假定为几种病毒，在人类肿瘤发生。公共卫生关系：这些实验将确定一种常见且相对无害的病毒腺病毒是否有可能导致儿童急性白血病。这些研究将促进我们对腺病毒生物学许多方面的理解，包括这种病毒在白色血细胞中鲜为人知的复制周期和新生儿中腺病毒感染的频率。这项工作可以为早期检测提供基础，并帮助开发一种简单的治疗儿童最常见癌症的方法。