Thymic epithelial genotype influences the production of recombinant leukemogenic retroviruses in mice

Abstract

By using T, oligonucleotide fingerprinting and mapping techniques, we analyzed the genomic structure of retroviruses produced by thymocytes and splenocytes of reciprocal bone marrow-and thymus-grafted chimeras. We found that the genetic factor(s) derived from NZB mice that suppresses the development of thymic leukemia in (AKR x NZB)F1 mice also prevents the formation of recombinant leukemogenic viruses and the expression of preleukemic changes in the (AKR x NZB)F1 thymocytes. The NZB mouse gene or genes appeared to exert this suppressive effect by acting on the thymic reticuloepithelial cells and not on the thymic lymphocytes of (AKR x NZB)Fl hybrids. Prospective studies with thymic epithelial grafts from young mice showed that the AKR thymic epithelium could mediate the formation and expression of leukemogenic recombinant viruses and preleukemic changes in thymocytes that lead to the development of thymic leukemia, whereas the (AKR x NZB)Fl thymic epithelium was deficient in this regard. Our results also confirmed a previous observation that during in vivo generation of recombinant leukemogenic viruses, the acquisition of polytropic virus-related sequences in the 3' portion of the plSE gene and the U3 region and in the 5' part of the gp7O gene can occur independently.

The tandem direct repeats within the long terminal repeat of murine leukemia viruses are the primary determinant of their leukemogenic potential

“…Specific T1 oligonucleotides within this region were identified in Gross A and in several spontaneous leukemia ecotropic leukemogenic AKR MuLVs, but not in nonleukemogenic AKR MuLV (1,29,30). A good correlation could also be established between specific pi5E and U3 LTR sequences of several AKR mink cell focus-forming MuLVs and their leukemogenicity (3,6,23,38). However, because of the methods used, these studies could not rule out the presence of other modifications in other parts of the genome as being critical in leukemogenesis, nor could they establish a causal link between the specific modifications identified and leukemogenicity.…”

“…Studies with in vivo-derived recombinants between oncogenic and nononcogenic avian leukosis viruses have revealed that at least two regions determine their oncogenic potential (35,39). Characterization of MuLVs isolated from leukemic mouse tissues has established that specific point mutations or sequence modifications or both which are generated by recombination within p15E and U3 long terminal repeat (LTR) sequences correlated very closely with the leukemogenic potential of these viruses (1,3,6,23,30,38,42). However, these studies could not establish whether these sequences were necessary and sufficient to account for the oncogenic potential of these viruses, nor could they exclude the involvement of other parts of the virus genome in the development of the disease.…”

Virological events leading to spontaneous AKR thymomas

“…However, there are a number of lines of evidence which suggest that (a) Bxv-J is involved in the initial recombination and (b) generation or selection of the recombinant viruses might occur in cells other than thymocytes. First, viruses with the structures predicted from recombination between ecotropic virus and Bxv-1 have been isolated by cocultivation from the cells of thymuses from young AKR mice, whereas Akv with polytropic gp7O substitutions characteristic in size of those found in type I MCF viruses have not been observed (12,16,17,64). Second, genome-length RNAs with xenotropic LTR sequences but lacking altered env genes have been detected in RNA extracted from the thymuses of 2-month-old AKR mice (35).…”

At least four viral genes contribute to the leukemogenicity of murine retrovirus MCF 247 in AKR mice

“…Previous studies from our laboratory (23,25,29,30,38) and others (3,4,11,34,35,42) have identified sequences that distinguish the genomes of oncogenic MCF viruses such as MCF 247 from closely related nononcogenic MCF or ecotropic retroviruses. Nucleotide sequencing in combination with RNase T1 fingerprints showed that leukemogenic MCF viruses of inbred mice differ from their ecotropic parents in sequences encoding the amino-terminal two-thirds of the viral envelope glycoprotein (gp70) and in the U3 region of the long terminal repeat (LTR).…”