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：
7584310
负责人：
David Arnold Ornelles
金额：
$ 42.63万
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/7584310
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）：急性白血病是童年最常见的恶性肿瘤，长期以来一直怀疑具有感染性病因。我们假设普通物种C腺病毒是某些急性儿童白血病的起始步骤。该假设是基于这样的观察结果：腺病毒DNA在新生儿的血液中更常见，后来患有急性淋巴细胞白血病，而不是在不发展白血病的儿童的血液中。额外的支持来自在Ornelles和Gooding Laborator中进行的观察结果，表明淋巴病毒祖细胞的腺病毒感染可能会产生易位携带细胞的扩展克隆，这是儿童白血病发育的起点。本应用中提出的研究将通过以下特定目的检验该假设：（1）评估产前感染与物种C腺病毒，白血病相关易位的发生以及使用存档的Guthrie卡片和新鲜的绳索血液的最终发展。（2）阐明腺病毒对淋巴样细胞中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）评估白血病细胞和造血祖细胞中腺病毒的腺病毒复制和细胞病理学。本应用中提出的研究将直接检验物种C腺病毒感染是导致儿童白血病的一系列事件的一步。此外，这项工作将确定影响淋巴病细胞中腺病毒复制的细胞基因，并确定使用该病毒的产前感染的频率。这些研究可能会为人类肿瘤发生的几种病毒的撞击机制提供支持。公共卫生相关性：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急性儿童白血病。这些研究将提高我们对腺病毒生物学许多方面的理解，包括该病毒在白细胞中鲜为人知的复制周期以及新生儿中腺病毒感染的频率。这项工作可以为早期测试提供基础，并有助于为最常见的儿童癌症开发一种简单的治疗方法。