TUMORIGENIC POTENTIAL OF A RECOMBINANT RETROVIRUS CONTAINING SEQUENCES FROM MOLONEY MURINE LEUKEMIA-VIRUS AND FELINE LEUKEMIA-VIRUS

A recombinant retrovirus, termed MoFe2-MuLV, was constructed in which the U3 region of T-lymphomagenic Moloney murine leukemia virus (Mo-MuL V) was replaced by that of FeLV-945, a provirus of unique long termina l repeat (LTR) structure identified only in non-T-cell, non-B-cell lym phomas of the domestic cat, The LTR of FeLV-945 is unusual in that it contains only a single copy of the transcriptional enhancer followed 2 5 bp downstream by a 21-bp sequence in triplicate in tandem. Infectivi ty of MoFe2-MuLv was demonstrated in vitro in SC-1 cells and in vivo i n neonatal NIH-Swiss mice. tumors occurred in MoFe2-MuLV-infected anim als following a latency period of 4 to 10 months (average, 6 months), The results of Southern blot analysis of the T-cell receptor beta locu s demonstrated that all tumors were lymphomas of T-cell origin, MoFe2- MuLV LTRs were amplified bt PCR from tumor DNA and were characterized by nucleotide sequence analysis. LTRs from the tumors that occurred wi th relatively shorter latency predominantly retained the original MoFe 2-MuLV sequence intact and unaltered, Tumors that occurred with relati vely longer latency contained LTRs that also retained the 21-bp sequen ce triplication characteristic of tile original virus but had acquired various duplications of enhancer sequences, The repeated identificati on of enhancer duplications in late-appearing tumors suggests that the duplication affords a selective advantage although apparently not in the efficient induction of T-cell lymphoma. Proto-oncogenes known to b e targets of insertional mutagenesis in the majority of Mo-MuLV-induce d tumors or in feline non-T-cell, non-B-cell lymphomas were shown not to be rearranged in any tumor examined. Mink cell focus-inducing (MCF) proviral DNA was readily detectable in some, but not all, tumors, The presence or absence of MCF did not correlate with the kinetics of tum or induction, These studies indicate that the single-enhancer, triplic ation-containing FeLV LTR, typical of non-T-cell, non-B-cell lymphomas in cats is competent in the induction of T-cell lymphoma in mice, The findings suggest that the mechanism of MoFe2-MuLV-mediated lymphomage nesis may differ from that of Mo-MuLV-mediated disease, considering th e possible involvement of novel oncogenes and the variable presence of MCF recombinants.