B-CELL LYMPHOMA INDUCTION BY AKV MURINE LEUKEMIA VIRUSES HARBORING ONE OR BOTH COPIES OF THE TANDEM REPEAT IN THE U3 ENHANCER

Akv is an endogenous, ecotropic murine leukemia virus (MuLV) of the AK R strain. It has served as a prototype nonpathogenic or weakly pathoge nic reference virus for studies of closely related potent lymphomageni c viruses such as the T-lymphomagenic SL3-3, We here report that Akv a nd an Akv mutant (Akv1-99) with only one copy of the 99-bp transcripti onal enhancer induce malignant lymphomas with nearly 100% incidence an d mean latency periods of 12 months after injection into newborn NMRI mice. Molecular analysis of tumor DNA showed that the majority of the tumors were of the B-cell type. Sequence analysis of proviral transcri ptional enhancers in DNA of B-cell lymphomas revealed conservation of the enhancer sequence, as well as a lack of sequence duplications of t he Akvl-99 variant, while the repeat copy number in Akv was subject to fluctuations. In support of a B-cell specificity of the Akv enhancer, a murine plasmacytoma cell line was found to sustain three-to fivefol d-higher transient transcriptional activity upon the Akv and Akvl-99 e nhancers than upon the enhancer of the T-lymphomagenic SL3-3 MuLV. Thu s, the overall picture is that Akv MuLV possesses a B-lymphomagenic po tential and that the second copy of the 99-bp sequence seems to be of minor importance for this potential. However, in one animal the lympho mas induced by Akv1-99 were of the T-cell type. Among the 24 tumors an alyzed only this one harbored a clonal proviral integration in the c-m yc locus. This provirus had undergone a duplication of a 113-bp sequen ce of the enhancer region, partly overlapping with the 99-bp repeat of Akv, as well as a few single nucleotide alterations within and outsid e the repeats, Taken together with previous studies, our results sugge st that T-versus B-lymphomagenic specificity of the enhancer is govern ed by more than one nucleotide difference and that alterations in bind ing sites for transcription factors of the AML1 and nuclear-factor-1 f amilies may contribute to this specificity.