Recurring proviral integration suggests a role for proto-oncogene activation in thymomas induced with Mo-MuLV-rescued BCR/ABL virus

Abstract

Intrathymic injection of Moloney murine leukemia virus (Mo-MuLV)-pseudotyped bcr-abl retrovirus (bcr-abl/M) causes thymic lymphoma but only after a prolonged latent period similar to that seen after intrathymic injection of Mo-MuLV alone. Since thymomas induced by Mo-MuLV show recurring proviral integration near certain cellular proto-oncogenes, it was reasoned that if the pathogenesis of bcr-abl/M thymomas is affected by viral integration, then it may be possible to detect proviral insertion near common Mo-MuLV integration sites in bcr-abl-induced thymomas. A panel of thymomas induced by intrathymic injection of Mo-MuLV, Abelson murine leukemia virus (A-MuLV), or the bcr-abl/M virus was analyzed for proviral integration near c-myc, N-myc, Pim-1, and Mlvi-1 loci that are frequently occupied by provirus in Mo-MuLV-induced T cell lymphomas, and for integration near Ahi-1 that is often occupied in A-MuLV/M-induced pre-B cell lymphoma. As expected, thymomas induced with Mo-MuLV showed frequent rearrangements in these loci while thymomas induced with A-MuLV/M (which does not require Mo-MuLV) did not. The bcr-abl/M-induced tumors also showed recurring proviral integration near c-myc, Pim-1 and Mlvi-1, albeit at a lower frequency than seen in the Mo-MuLV tumors. Unexpectedly, four independent thymomas that were clearly of T cell origin demonstrated proviral integration within the Ahi-1 region which was previously thought to only occur in A-MuLV/M induced pre-B cell lymphoma. These observations suggest that recurring proviral insertion in c-myc, Pim-1, Mlvi-1, and Ahi-1 may provide a selective advantage for bcr-abl/M transformed T lymphoid cells. This model may provide a tool for identifying cellular genes that can cooperate with bcr-abl in lymphoid transformation.