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

描述(申请人提供)：急性白血病，最常见的儿童恶性肿瘤，长期以来一直被怀疑有感染性病原学。我们推测，常见的C型腺病毒是导致某些急性儿童白血病的始动步骤。这一假说是基于这样一种观察，即C型腺病毒DNA在后来发展为急性淋巴细胞白血病的新生儿的血液中比在没有发展为白血病的儿童的血液中更常见。Ornelle和Gooding实验室的观察表明，腺病毒感染淋巴祖细胞可以产生携带易位的细胞的扩增克隆，这是儿童白血病发展的起点，这也得到了额外的支持。这项申请中提出的研究将通过以下具体目标来检验这一假设：(1)使用格思里档案卡和新鲜脐带血，评估产前感染C类腺病毒、白血病相关易位的发生和白血病最终发展之间的一致性。(2)研究腺病毒对淋巴样细胞DNA修复的影响。(3)观察腺病毒感染对淋巴细胞DNA完整性的影响。(4)研究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改变。这项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一系列事件中的一步的可能性。此外，这项工作将确定影响淋巴细胞中腺病毒复制的细胞基因，并确定产前感染该病毒的频率。这些研究可能会为人类肿瘤发生中的打了就跑的机制提供支持，这种机制已经被假设为几种病毒。与公共卫生相关：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的许多方面的理解，包括这种病毒在白细胞中鲜为人知的复制周期以及腺病毒在新生儿中的感染频率。这项工作可以为早期测试提供基础，并有助于开发一种治疗最常见的儿童癌症的简单方法。

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.