Date of Award
Doctor of Philosophy (PhD)
The common species C adenoviruses infect more than 80% of the human population early in life. The virus can establish an asymptomatic persistent infection in mucosal-associated lymphocytes. Adenovirus has long been classified as DNA tumor virus, however it still has no established associations with any specific cancer. This phenomenon may be explained by the model of hit-and-run viral oncogenesis, which proposes that a virus can infect a cell population, causing oncogenic mutations (hit) that in turn inhibit the virus from persisting in the cancerous cell progeny (run). One type of cancer in particular, childhood precursor B-cell acute lymphoblastic leukemia, is suspected of having an infectious cause, yet no viral agent has been conclusively linked to the disease. Childhood acute lymphoblastic leukemia is associated with frequently occurring chromosomal translocations that encode fusion proteins. ETV6/RUNX1 is the most commonly found translocation and the only one to be associated with the infectious etiology of the disease. We hypothesized that adenovirus may be an agent capable of initiating childhood precursor B-cell acute lymphoblastic leukemia but that the virus is evicted from cancer cells by the activities of the ETV6/RUNX1 leukemic fusion gene. We found that adenovirus retention in a B-cell model of persistence was inhibited by direct binding of the ETV6/RUNX1 fusion gene to the viral genome. This loss of virus was dependent on histone deacetylation activities, but was not impacted by NF-κB interference, selective cell death of infected cells, or known interactions of RUNX1 with viral protein. Further, epigenetic changes induced in cells following viral infection were still present after viral eviction from the cells, which demonstrates that viral retention is unnecessary for sustained repression of cellular genes. Because latency is likely related to viral retention in B-cells, we also studied how NF-κB control of the adenovirus E3 region and expression of the contained adenovirus death protein (ADP) gene could effect viral latency in lymphocytes. We failed to find specific activation of E3 region genes with NF-κB activation through PMA/Ionomycin. ADP was necessary for lytic infection in lymphocytes, but not epithelial cells, signifying differences in regulation of ADP between these cell types.
Wilms, Hans T., "Adenovirus “Hit-And-Run” Eviction From B-Cells Harboring Leukemic Runx1 Fusion Genes And Adp Controlled Latency In Lymphocytes." Dissertation, Georgia State University, 2017.
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