Leukemogenic activity of b-ecotropic c-type retroviruses isolated from tumors induced by radiation leukemia virus (radlv-rs) in c57bl/6 mice.

In addition to the endogenous N-tropic and xenotropic retroviruses in C57BL/6 mice, B-tropic viruses which result from recombination between the endogenous parental viruses have frequently been isolated from old or leukemic animals. A thymotropic B-tropic virus was also isolated after many serial in vivo passages from tumors induced by RadLV initially obtained by Kaplan from radiation-induced thymic lymphosarcomas. Although this agent was shown to be responsible for the capacity of Kaplan RadLV to induce thymic lymphosarcomas (TLS), the oncogenic role of C57BL/6 B-tropic viruses has never been demonstrated. Three B-tropic viruses (T1223/B, T128/B and T98/B) were isolated from Duplan (RadLV-Rs) extract which, like Kaplan isolate, originates from radiation-induced TLS. Whereas thymotropism was retained by Kaplan extract, extra-thymic lymphosarcomas were preferentially induced by RadLV-Rs. Although the B-tropic isolates emerged from recombinational events between the two endogenous parental viruses, their recombination pattern and their biological in vitro properties indicated that each of them was unique. The present experiments demonstrate, firstly, that in no case was an early disease ressembling that induced by RadLV-Rs observed; secondly, that the three viruses induced a high percentage of extra-thymic lymphomas whose latencies always exceeded 400 days; thirdly, that irrespective of the cloned virus a similar pattern of leukemogenesis was observed; fourthly, that B lymphomas predominated over thymic and extra-thymic T or null lymphoma and erythromyeloid leukemias. The injected viruses shortened the latencies and increased the frequency of the spontaneous disease observed in old animals, which suggests that in both cases leukemogenesis may result from closely related mechanisms. Our observation that the leukemic process developed after a shorter latent period in animals injected at 400 days of age than in those injected at birth or at 30 days of age strongly suggests that the injected viruses need to undergo a second recombination with the endogenous viruses expressed in old mice before they are capable of inducing lymphomas. This hypothesis is supported by the result of the transplantation assay. It does not exclude the possibility of an impairment of the immune responsiveness contributed to the accelerated leukemogenesis in old animals. Thymic and extra-thymic T lymphomas occurred preferentially in mice injected at birth, indicating that T-populations present at this age might be necessary for the newly generated T-tropic recombinants to emerge, replicate or find their target cells.