LONG TERMINAL REPEAT ENHANCER CORE SEQUENCES IN PROVIRUSES ADJACENT TO C-MYC IN T-CELL LYMPHOMAS INDUCED BY A MURINE RETROVIRUS

The transcriptional enhancer in the long terminal repeat (LTR) of the T-lymphomagenic retrovirus SL3-3 differs from that of the nonleukemoge nic virus Akv at several sites, including a single base pair differenc e in an element termed the enhancer core. Mutation of this T-A base pa ir to the C-G sequence found in Akv significantly attenuated the leuke mogenicity of SL3-3. Thus, this difference is important for viral leuk emogenicity. Since Akv is an endogenous virus, this suggests that the C-G in its core is an adaptation to being minimally pathogenic. Most t umors that occurred in mice inoculated with the mutant virus, called S AA, contained proviruses with reversion or potential suppressor mutati ons in the enhancer core. We also found that the 72-bp tandem repeats constituting the viral enhancer could vary in number. Most tumors cont ained mixtures of proviruses with various numbers of 72-bp units, usua lly between one and four. Variation in repeat number was most likely d ue to recombination events involving template misalignment during vira l replication. Thus, two processes during viral replication, misincorp oration and recombination, combined to alter LTR enhancer structure an d generate more pathogenic variants from the mutant virus. In SAA-indu ced tumors, enhancers of proviruses adjacent to c-myc had the largest number of core reversion or suppressor mutations of all of the viral e nhancers in those tumors. This observation was consistent with the hyp othesis that one function of the LTR enhancers in leukemogenesis is to activate proto-oncogenes such as c-myc.