Abstract
Avian leukosis virus (ALV) is a simple retrovirus that causes a wide range of tumors in chickens, the most common of which are B-cell lymphomas. The viral genome integrates into the host genome and uses its strong promoter and enhancer sequences to alter the expression of nearby genes, frequently inducing tumors. In this study, we compare the preferences for ALV integration sites in cultured cells and in tumors, by analysis of over 87,000 unique integration sites. In tissue culture we observed integration was relatively random with slight preferences for genes, transcription start sites and CpG islands. We also observed a preference for integrations in or near expressed and spliced genes. The integration pattern in cultured cells changed over the course of selection for oncogenic characteristics in tumors. In comparison to tissue culture, ALV integrations are more highly selected for proximity to transcription start sites in tumors. There is also a significant selection of ALV integrations away from CpG islands in the highly clonally expanded cells in tumors. Additionally, we utilized a high throughput method to quantify the magnitude of clonality in different stages of tumorigenesis. An ALV-induced tumor carries between 700 and 3000 unique integrations, with an average of 2.3 to 4 copies of proviral DNA per infected cell. We observed increasing tumor clonality during progression of B-cell lymphomas and identified gene players (especially TERT and MYB) and biological processes involved in tumor progression.
Highlights
Avian leukosis virus (ALV) is a simple retrovirus that causes cancer, primarily B-cell lymphomas in chickens [1,2,3]
Our study provides new insights into the changes during lymphoma initiation, progression, and metastasis, as a result of selection for specific ALV integration sites
ALV integration is enriched within genes in cultured cells and in tumors Via deep sequencing, we analyzed approximately 87,000 unique ALV integration sites (UISs) in tissue culture cells and in tumors, as summarized in S1 Table
Summary
Avian leukosis virus (ALV) is a simple retrovirus that causes cancer, primarily B-cell lymphomas in chickens [1,2,3]. The ALV genome does not contain a viral oncogene and induces aberrant host gene expression via use of strong viral enhancer and promoter elements. Relative to other well studied retroviruses like HIV-1 and MLV, ALV was shown to integrate relatively randomly into the host genomic DNA, with little bias for genomic features [4,5,6,7]. The FACT (facilitates chromatin transcription) complex, a chromatin remodeler, was recently reported to promote ALV integration [8]. ALV-induced lymphomas develop in a multistage process, appearing initially as neoplastic follicles in the bursa, some of which develop into primary bursal tumors. We are studying rapidonset lymphomas, which develop in less than 3 months after infection of chicken embryos with ALV [10,11]
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