Enhancer activity correlates with the oncogenic potential of avian retroviruses

Avian retroviruses lacking an oncogene, such as Rous-associated virus 1 (RAV-1), RAV-2, and td mutants of Rous sarcoma virus (RSV), can nevertheless cause leukemias and other neoplastic diseases. During this process, viral DNA integrates near a cellular proto-oncogene, such as c-myc, and thus de-regulates its expression. The virus RAV-0, on the other hand, is known to be non-oncogenic even in long-term in vivo infections of domestic chickens. The major difference between oncogenic and non-oncogenic viruses is found within the U3 region of the long terminal repeat (LTR) which is known to harbor the promoter and enhancer elements. We therefore wanted to see whether viral oncogenicity was correlated with enhancer activity. Using a variety of techniques (including the SV40 'enhancer trap' from which we obtained RSV-SV40 recombinant viruses), we demonstrate that a strong enhancer exists within the LTRs of both RSV and RAV-1. In contrast, no enhancer is present in RAV-0, although RAV-0 has functional promoter elements. Our data therefore strongly support a concept of oncogenesis by enhancer insertion.