Mobility and integration sites of a murine C57BL/6 melanoma endogenous retrovirus involved in tumor progression in vivo

Tumor development is a multistep process in which both genetic and epigenetic events cooperate for the emergence of a malignant clone with metastatic properties. The possibility that endogenous retroviruses promote the expansion of a neoplastic clone by subverting immunosurveillance has been proposed and recently demonstrated in the case of the B16 murine melanoma, which spontaneously express the melanoma-associated retrovirus (MelARV). Indeed, knocking down, by RNA interference, this endogenous retrovirus resulted in the rejection of the tumor cells in immunocompetent mice, without any alteration of their transformed phenotype. Here, we characterize the MelARV proviruses present in the B16 melanoma. Complete sequencing of the viral genomic RNA and characterization of the integration sites within both the B16 tumor cells and a subline selected in vivo for increased metastatic activity disclosed mobility of the element with new proviral insertions targeting critical genes and altering their transcriptional profile. The results show that MelARV can act both at the genetic level, inducing mutations by insertion, and at the epigenetic level, promoting immunosuppression of the host. These properties may as well be relevant to human tumors, such as germline tumors and melanoma, where endogenous retroviruses are active. © 2006 Wiley-Liss, Inc.