Mrvil, a common MRV integration site in BXH2 myeloid leukemias, encodes a protein with homology to a lymphoid-restricted membrane protein Jaw1

Ecotropic MuLVs induce myeloid leukemia in BXH2 mice by insertional mutagen esis of cellular protooncogenes or tumor suppressor genes, Disease genes ca n thus be identified by viral tagging as common sites of viral integration in BXH2 leukemias. Previous studies showed that a frequent common integrati on site in BXH2 leukemias is the NJ1 tumor suppressor gene. Unexpectedly, a bout half of the viral integrations at Nf1 represented a previously undisco vered defective nonecotropic virus, termed MRV, Because other common integr ation sites in BXH2 leukemias encoding protooncogenes contain ecotropic rat her than MRV viruses, it has been speculated that MRV viruses may selective ly target tumor suppressor genes. To determine if this were the case, 21 MR V-positive BXH2 leukemias were screened for new MRV common integration site s. One new site, Mrvi1 was identified that was disrupted by MRV in two of t he leukemias. Ecotropic virus did not disrupt Mrvi1 in 205 ecotropic virus- positive leukemias, suggesting that Mrvi1 is specifically targeted by MRV, Mrvi1 encodes a novel protein with homology to Jaw1, a lymphoid restricted type II membrane protein that localizes to the endoplasmic reticulum, MRV i ntegration occurs at the 5' end of the gene between two differentially used promoters. Within hematopoietic cells, Mrvi1 expression is restricted to m egakaryocytes and some myeloid leukemias, Like Jaw1, which is downregulated during lymphoid differentiation, Mrv1 is do downregulated during monocytic differentiation of BXH2 leukemias, Taken together, these data suggest that MRV integration at Mrvi1 induces myeloid leukemia by altering the expressi on of a gene important for myeloid cell growth and/or differentiation. Expe riments are in progress to test whether Mrvi1 is a tumor suppressor gene.