title: B-Cell lymphoma induction by akv murine leukemia viruses harboring one or both copies of the tandem repeat in the U3 enhancer.
abstract: Akv is an endogenous, ecotropic murine leukemia virus (MuLV) of the AKR strain. It has served as a prototype nonpathogenic or weakly pathogenic reference virus for studies of closely related potent lymphomagenic viruses such as the T-lymphomagenic SL3-3. We here report that Akv and an Akv mutant (Akv1-99) with only one copy of the 99-bp transcriptional enhancer induce malignant lymphomas with nearly 100% incidence and 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 transcriptional enhancers in DNA of B-cell lymphomas revealed conservation of the enhancer sequence, as well as a lack of sequence duplications of the Akv1-99 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 fivefold-higher transient transcriptional activity upon the Akv and Akv1-99 enhancers than upon the enhancer of the T-lymphomagenic SL3-3 MuLV. Thus, the overall picture is that Akv MuLV possesses a B- lymphomagenic potential and that the second copy of the 99-bp sequence seems to be of minor importance for this potential. However, in one animal the lymphomas induced by Akv1-99 were of the T-cell type. Among the 24 tumors analyzed only this one harbored a clonal proviral integration in the c-myc locus. This provirus had undergone a duplication of a 113-bp sequence of the enhancer region, partly overlapping with the 99-bp repeat of Akv, as well as a few single nucleotide alterations within and outside the repeats. Taken together with previous studies, our results suggest that T- versus B-lymphomagenic specificity of the enhancer is governed by more than one nucleotide difference and that alterations in binding sites for transcription factors of the AML1 and nuclear-factor-1 families may contribute to this specificity.
authors.affiliation: Department of Molecular and Structural Biology, University of Aarhus, DK-8000 Aarhus C, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Lovmand
authors.forename: A B
authors.initials: AB
authors.lastname: Sorensen
authors.forename: J
authors.initials: J
authors.lastname: Schmidt
authors.forename: M
authors.initials: M
authors.lastname: Ostergaard
authors.forename: A
authors.initials: A
authors.lastname: Luz
authors.forename: F S
authors.initials: FS
authors.lastname: Pedersen
mesh_terms: D016475:3T3 Cells; D000818:Animals; D004273:DNA, Neoplasm / Q000032:analysis; D004742:Enhancer Elements, Genetic; D015321:Gene Rearrangement; D016259:Genes, myc; D007150:Immunohistochemistry; D009052:Leukemia Virus, Murine / Q000235:genetics* / Q000472:pathogenicity; D016393:Lymphoma, B-Cell / Q000209:etiology*; D051379:Mice; D008806:Mice, Inbred AKR; D017354:Point Mutation; D012091:Repetitive Sequences, Nucleic Acid; D014407:Tumor Cells, Cultured; D016662:Virus Integration
chemical_list: D004273:DNA, Neoplasm