Lovmand J, Sorensen A B, Schmidt J, Ostergaard M, Luz A, Pedersen F S
Department of Molecular and Structural Biology, University of Aarhus, DK-8000 Aarhus C, Denmark.
J Virol. 1998 Jul;72(7):5745-56. doi: 10.1128/JVI.72.7.5745-5756.1998.
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.
Akv是AKR株的一种内源性嗜亲性鼠白血病病毒（MuLV）。它已作为一种原型非致病性或弱致病性参考病毒，用于研究密切相关的强效淋巴瘤病毒，如致T淋巴细胞淋巴瘤的SL3-3病毒。我们在此报告，Akv和仅含有一个99碱基对转录增强子拷贝的Akv突变体（Akv1-99），在注射到新生NMRI小鼠后，可诱导恶性淋巴瘤，发病率近100%，平均潜伏期为12个月。对肿瘤DNA的分子分析表明，大多数肿瘤为B细胞类型。对B细胞淋巴瘤DNA中前病毒转录增强子的序列分析显示，增强子序列保守，且Akv1-99变体缺乏序列重复，而Akv中的重复拷贝数存在波动。为支持Akv增强子的B细胞特异性，发现一种鼠浆细胞瘤细胞系在Akv和Akv1-99增强子作用下的瞬时转录活性比致T淋巴细胞淋巴瘤的SL3-3 MuLV增强子高3至5倍。因此，总体情况是Akv MuLV具有B淋巴瘤致瘤潜力，且99碱基对序列的第二个拷贝对此潜力似乎不太重要。然而，在一只动物中，Akv1-99诱导的淋巴瘤为T细胞类型。在分析的24个肿瘤中，只有这一个在c-myc基因座存在克隆性前病毒整合。该前病毒经历了增强子区域113碱基对序列的重复，部分与Akv的99碱基对重复序列重叠，以及重复序列内外的一些单核苷酸改变。结合先前的研究，我们的结果表明，增强子的T细胞与B细胞淋巴瘤致瘤特异性由不止一个核苷酸差异决定，AML1和核因子-1家族转录因子结合位点的改变可能导致这种特异性。
