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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Virology - A Study Section (VIRA)
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Daschner, Phillip J
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Murali, V K; Ornelles, D A; Gooding, L R et al. (2014) Adenovirus death protein (ADP) is required for lytic infection of human lymphocytes. J Virol 88:903-12
Turner, Roberta L; Wilkinson, John C; Ornelles, David A (2014) E1B and E4 oncoproteins of adenovirus antagonize the effect of apoptosis inducing factor. Virology 456-457:205-19
Furuse, Yuki; Ornelles, David A; Cullen, Bryan R (2013) Persistently adenovirus-infected lymphoid cells express microRNAs derived from the viral VAI and especially VAII RNA. Virology 447:140-5
Zhang, Yange; Huang, Wen; Ornelles, David A et al. (2010) Modeling adenovirus latency in human lymphocyte cell lines. J Virol 84:8799-810
Honkaniemi, E; Talekar, G; Huang, W et al. (2010) Adenovirus DNA in Guthrie cards from children who develop acute lymphoblastic leukaemia (ALL). Br J Cancer 102:796-8