Our studies focus on the molecular mechanisms of retrovirus-induced murine lymphoma/leukemia. We have utilized non-random retrovirus integrations in lymphomas as genetic markers to clone and characterize somatically acquired proviruses. This approach can provide a molecular access for the isolation of novel cellular genes affected by retrovirus insertional mutagenesis. In a study to characterize the Evi5 locus, a common integration site of retroviruses in T cell lymphomas, we have demonstrated that Evi5 is evolutionarily well conserved and that in some T cell lymphomas the coding region of Evi5 gene was truncated as a result of virus integrations. We have determined that Evi5 is a nuclear phosphoprotein whose expression alters during the cell cycle. Further studies using molecularly mutated Evi5 should shed light on how Evi5 is involved in T cell lymphomagenesis as well as helping to define the normal function of this gene. As part of our larger effort to understand the pathogenic role of retroviruses in lymphomagenesis, we have undertaken investigations on provirus insertion in ecotropic virus-associated B cell malignancies of NFS mice. Multiple genetic events may be involved in tumor induction and these may be identifiable by characterizing the cellular targets of somatically acquired provirus integration. One cloned provirus integration site, designated Bei1 (B cell lymphoma ecotropic retrovirus integration site 1), was found to be expressed in various lymphoma/leukemia, while expression in normal tissues was restricted to liver, testis and brain. Bei1 was mapped to mouse chromosome 2 in a region where frequent chromosome aberrations have been detected that correlate with susceptibility to radiation- and virus-induced myeloid leukemia. Another provirus integration site, designated Bei2, is also associated with an abnormal expression pattern in mouse lymphoma/leukemia. Chromosomal mapping studies suggest that the human counterpart of the Bei2 locus may reside on 12p13 where translocation breakpoints were found in a group of aggressive human lymphoma/leukemias. Both Bei1 and Bei2 may play a causal role in the development of mouse lymphoma/leukemia. We are in the process of isolating cDNA of these two candidate disease genes to study their functions.
