Retroviral gene insertion in breast milk mediated lymphomagenesis

Abstract

We have demonstrated breast milk transmitted MoMuLV-ts1 retrovirus infection and subsequent lymphoma development in offspring of uninfected mothers suckled by infected surrogate mothers. Additionally, we have shown that the lymphoma development occurs as a result of viral gene integration into host genome. A total of 146 pups from Balb/C mice were divided into 5 groups; one control and 4 experimental. All offspring suckled from surrogate infected or control mothers, except one group of infected pups left with their biological mothers. Thirteen of 91 infected pups developed lymphoma. Inverse-PCR, DNA cloning, and quantitative real-time PCR (qRT-PCR) were used to study the virus integration sites (VIS) and alterations in gene expression. VIS were randomly distributed throughout the genome. The majority of insertion sites were found in chromosomes 10, 12 and 13. A total of 209 proviral genomic insertion sites were located with 52 intragenic and 157 intergenic sites. We have identified 29 target genes. Four genes including Tacc3, Aurka, Gfi1 and Ahi1 showed the maximum upregulation of mRNA expression. These four genes can be considered as candidate genes based on their association with cancer. Upregulation of these genes may be involved in this type of lymphoma development. This model provides an important opportunity to gain insight into the relationship of viral gene insertion into host genome and development of lymphoma via natural transmission route such as breast milk.