This proposal is based on two findings. The first is that in AKR mice experimental virus-induced leukemias of the T-cell lineage exhibit a high frequency (65%) of proviral integrations into the c-myc locus. The second and salient observation is that radiation-induced thymomas in BALB/c harbor, in several instances, a precise rearrangement of DNA sequences immediately upstream of c-myc. No new ecotropic or env-recombinant proviruses appear to be involved in this case. Emphasizing this second finding, we propose to examine in depth the role of c-myc expression in T-cell leukemogenesis. We shall determine whether the alteration of this locus in radiation-induced disease reflects a chromosomal translocation, or a cassette-like insertion of new sequence. In either case we shall clone the new sequence upstream of c-myc and sequence it and its normal homologue in order to explore possible mechanisms of transposition. The cloned sequence will be compared with other retrovirus-like elements and with putative enhancer regions of the T-cell receptor, as well as with immunoglobulin enhancers and other known enhancer-like sequences. The effects of the sequence under study on c-myc transcription will be analyzed in detail. Possible changes at the DNA level in other oncogenes specifying nuclear products will also be sought in radiation leukemias in which the c-myc locus appears normal. Retroviral vectors will be constructed, containing myc cDNA with and without the new upstream sequence. The influence of alternative viral LTRs on T-cell leukemogenesis vs. other hemopoietic neoplasms will be studied; alternatively, the LTR effect will be suppressed, to expose myc-associated transcriptional control. In vitro infection of thymocytes and other T-cell populations will be used to study growth regulation by myc.
| Sorrentino, V; McKinney, M D; Giorgi, M et al. (1988) Expression of cellular protooncogenes in the mouse male germ line: a distinctive 2.4-kilobase pim-1 transcript is expressed in haploid postmeiotic cells. Proc Natl Acad Sci U S A 85:2191-5 |
| Sorrentino, V; Drozdoff, V; McKinney, M D et al. (1986) Potentiation of growth factor activity by exogenous c-myc expression. Proc Natl Acad Sci U S A 83:8167-71 |
