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

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。

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.