ROLE OF RAF AND MYC ONCOGENES IN TRANSFORMATION IN VIVO AND IN VITRO

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In order to evaluate the target cell range for transformation by v- raf, as well as to determine whether v-raf is capable of inducing transformation by itself or requires interaction with a second oncogene, myc, a series of recombinant viruses was constructed with either or both viral oncogenes on the 3611-murine sarcoma virus (MSV) background. A combination of both oncogenes in an infectious murine retrovirus (J-2) induces hematopoietic neoplasms, in addition to less prominent fibrosarcomas and pancreatic adenocarcinomas 1 to 3 weeks after inoculation. The hematologic neoplasms consist of immunoblastic lymphomas of T- and B-cell lineage, and erythroblastosis. In parallel to the synergistic action of both oncogenes on hematopoietic cells in vivo, we find that raf oncogene-induced transformation of bone marrow cells in culture is enhanced by the addition of myc, which by itself does not transform these cells when grown in standard media. We conclude that concomitant expression of raf and myc oncogenes in hematopoietic cells alters their respective transforming activities. The contribution of myc to this synergism was examined by using a series of recombinant murine retroviruses capable of expressing avian v-myc or mouse c-myc to study the effect of altered myc expression on hematopoietic/lymphoid cells. The v-myc-carrying virus, J-3, was shown to synergize with the mineral oil, pristane, in the induction of plasmacytomas, where it functionally replaces activation of c- myc by chromosomal translocation. With either interleukin-3 (IL- 3)- or IL-2-dependent cell lines, introduction of the recombinant viruses abrogated the requirement for IL-3 or Il-2 for growth, and associated with this was the suppression of c-myc expression. The findings suggest that myc is a component in the signal transduction pathway for IL-3 and IL-2 and support an autoregulatory mechanism of c-myc expression. In contrast to v- myc, expression of v-raf in primary lymphoid/hematopoietic cells has an immortalizing function without abrogating the requirement for IL-3 for growth.