IMPORTANCE OF A C-MYB BINDING-SITE FOR LYMPHOMAGENESIS BY THE RETROVIRUS SL3-3

All murine leukemia viruses (MuLVs) and related type C retroviruses co ntain a highly conserved binding site for the Ets family of transcript ion factors within the enhancer sequences in the viral long terminal r epeats (LTRs), The T-cell lymphomagenic MuLV SL3-3 (SL3-3) also contai ns a c-Myb binding site adjacent to the Ets site, The presence of this Myb site distinguishes SL3 from most other MuLVs, We tested the impor tance of these two sites for the lymphomagenicity of SL3-3. Mutation o f the Ets site had little effect on viral pathogenicity,, as it only s lightly extended the latency period to disease onset, In contrast, mut ation of the Myb site strongly inhibited pathogenicity; as only a mino rity of the inoculated mice developed tumors in the two mouse strains that were tested. All tumors that mere induced by either mutant appear ed to be lymphomas, and no evidence for reversion of either mutation w as detected. The effects of the Ets and Myb site mutations on transcri ptional activity of the SL3 LTR were tested by inserting the viral enh ancer sequences into a plasmid containing the promoter region of the c -myc gene linked to a reporter gene. Mutation the Myb site almost elim inated enhancer activity in T lymphocytes, while mutation of the Ets s ite had smaller effects, Thus, the effects of the enhancer mutations o n transcriptional activity in T cells paralleled their effects on vira l lymphomagenicity. The absence of the c-Myb site in the LTR enhancer of the weakly lymphomagenic MuLV, Akv, likely contributes to the lon p athogenicity of this virus relative to SL3-3, However, Moloney MuLV al so lacks the Myb site in its LTR, although it induces T-cell lymphomas with a potency similar to that of SL3-3. Thus, it appears that SL3-3 and Moloney MuLV evolved genetic determinants of T-cell lymphomagenici ty that are, at least in part, distinct.