Oncogenesis by Moloney murine leukemia virus

Abstract

Moloney murine leukemia virus (MoMuLV) is a retrovirus which lacks an oncogene. It is, however, highly oncogenic in rats and mice, in whom it induces thymic lymphomas. These lymphomas are clonal tumors and appear four to six months following virus inoculation. Although provirus integration is random in virus infected non-tumor cells, it shows regional specificity in these tumors, thus suggesting that insertional mutagenesis may play an important role in tumor induction and progression. Our studies have revealed four common DNA regions for provirus insertion in these tumors (Mlvi-1, Mlvi-2, Mlvi-3 and c-Myc), while studies from other laboratories have revealed two additional ones (pvt-1/mis-1 and pim-1). Mlvi-1, Mlvi-2 and Mlvi-3 represent three independent logi since there is no homology between them molecular clones that identify them and they map on different rat chromosomes. It is interesting however that two of them (Mlvi-1 and Mlvi-2), as well as pvt-1/mis-1, map to mouse chromosome 15 which is known to become trisomic in murine thymic lymphomas. In addition to the specificity of provirus integration, tumor induction is also associated with amplification of the proviral DNA. This amplification may be favored during oncogenesis because cells that carry insertion mutations in multiple oncogenes may exhibit growth advantage over cells in which only single insertion mutations have occurred. This could happen because the effect of these mutations may be additive or because there is a synergistic relationship between multiple loci during oncogenesis. This was indeed suggested by the appearance of concerted provirus insertions in Mlvi-1 and Mlvi-2. Alternatively, the amplification of the provirus during tumor induction may be selected because it provides for elevated levels of viral gene products that participate in the process of oncogenesis. Such products may be coded by sequences in the gag/pol region. We indeed present evidence here for a 2 kb tumor specific gag/pol transcript which is expressed in these thymomas. Our analysis of Mlvi-1 and Mlvi-2 has revealed the following. Mlvi-1 contains at least one open reading frame which is conserved among species and which preliminary evidence indicates may be expressed in the thymomas. Additionally Mlvi-1 appears to be present in more than one copy per haploid genome in both rats and humans. In Mlvi-2 we have shown the presence of a transcribed region downstream from the cluster of the integrated proviruses in the MoMuLV induced thymic lymphomas. However this transcript is expressed mostly in rat embryo fibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)