Increased induction of osteopetrosis, but unaltered lymphomagenicity, by murine leukemia virus SL3-3 after mutation of a nuclear factor 1 site in theenhancer

SL3-3 is a murine leukemia virus which is only weakly bone pathogenic but h ighly T-cell lymphomagenic. A major pathogenic determinant is the transcrip tional enhancer comprising several transcription factor binding sites, amon g which are three identical sites for nuclear factor 1 (NF1). We have inves tigated the pathogenic properties of NF1 site enhancer mutants of SL3-3. Tw o different mutants carrying a 3-bp mutation either in all three NF1 sites or in the central site alone were constructed and assayed in inbred NMRI mi ce. The wild type and both mutants induced lymphomas in all mice, with a me an latency period of 9 weeks. However, there was a considerable difference in osteopetrosis induction. Wild-type SL3-3 induced osteopetrosis in 11% of the mice (2 of 19), and the triple NF1 site mutant induced osteopetrosis i n none of the mice (0 of 19), whereas the single NF1 site mutant induced os teopetrosis in 56% (10 of 18) of the mice, as determined by X-ray analysis. A detailed histological examination of the femurs of the mice was carried out and found to support this diagnosis. Thus, the NF1 sites of SL3-3 are m ajor determinants of osteopetrosis induction, without determining lymphomag enesis. This conclusion was further supported by evaluation of the bone pat hogenicity of other SL3-3 enhancer variants, the lymphomagenicity of which had been examined previously. This evaluation furthermore strongly indicate d that the core sites, a second group of transcription factor binding sites in the viral enhancer, are necessary for the osteopetrosis induction poten tial of SL3-3.