RECOMBINANT RETROVIRUSES AND LEUKEMOGENESIS IN AKR STRAIN MICE

A complex pattern of murine leukemia virus (MuLV) expression is associated with the 'spontaneous' development of thymic leukemias in six to nine-month-old AKR strain mice. The AKR mouse genome contains endogenous MuLV proviruses of two major host range preferences, defined by the viral envelope gene products, gp70 and p15E: ecotropic MuLV, which replicate in murine cells, and xenotropic MuLV, which are restricted to heterologous species. Life-long expression of the ecotropic AKV MuLV begins in embryonic AKR mice and ecotropic-nonecotropic envelope gene recombinant MCF MuLV appear in the preleukemic and leukemic AKR thymus. This thesis describes the arrangement and structure of these MuLV proviruses in the AKR germ-line and thymus.; Multiple discrete ecotropic and nonecotropic MuLV specific hybridization probes, which map within and adjacent to the recombinant regions of two MCF viruses, discriminate between endogenous germ-line MuLV populations and show that MCF viruses arise by recombination during ontogeny (Chapter 2). The nucleotide sequence of the AKV envelope gene and surrounding regions (Chapter 3) defines the genetic map of the 3' half of AKV and suggests that the thymotropic host range of oncogenic MCF viruses may be a consequence of the juxtaposition of a nonecotropic gp70 receptor binding activity with an ecotropic p15E virus-cell membrane-fusion activity. Highly inbred AKR strain mice from the Jackson Laboratory (Bar Harbor, Maine) colony had differing numbers of germ-line ecotropic proviruses suggesting germ-line AKV reintegrations had occurred (Chapter 4, Nature 269, 865-868 {lcub}1982{rcub}).; Many recombinant MuLV proviruses, structurally analogous to oncogenic MCF viruses, appear unintegrated in the preleukemic thymus and integrated in the leukemic thymus (Chapters 5 and 6). The proviral ecotropic-nonecotropic recombination patterns are highly variable but in individual thymuses both the free and integrated proviral forms exhibit structural homogeneity. This suggests that the recombination events which create oncogenic MCF viruses are infrequent and may be a rate-limiting step in AKR leukemogenesis. The leukemic-cell population is of clonal cell origin, yet may exhibit multiple rearrangements of the immunoglobulin heavy-chain J segment exons (Chapter 7), suggesting that such rearrangements, which have been observed in T-cell lines, occur after viral transformation.