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Journal of Virology, March 2002, p. 2087-2099, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2087-2099.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Selection for c-myc Integration Sites in Polyclonal T-Cell Lymphomas

Section of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712

Received 20 September 2001/ Accepted 26 November 2001

Type B leukemogenic virus (TBLV) is highly related to mouse mammary tumor virus but induces rapidly appearing T-cell lymphomas in mice. Unlike other T-cell tumors induced by retroviruses, only 5 to 10% of TBLV-induced lymphomas have detectable viral integrations near c-myc by Southern blotting, whereas Northern blotting has shown that most tumors have two- to sixfold overexpression of c-myc RNA. In this report, PCR was used to demonstrate that at least 30% of these lymphomas have TBLV insertions near c-myc. Some tumors contained multiple TBLV proviruses in different locations and orientations, suggesting that the tumors are polyclonal. The integrated proviruses near c-myc had different numbers (two to four) of long terminal repeat (LTR) enhancer repeats, although LTRs with three-repeat enhancers dominated the proviral population. Passage of polyclonal tumors in immunocompetent mice and semiquantitative PCR revealed that only cells with particular integrations were selected for growth. In three of six tumors tested, proviruses containing four-repeat enhancers near c-myc were selected during tumor passage. Since tumor cell selection may be accomplished by overexpression of c-myc RNA due to proximity to the unique TBLV LTR enhancer, we inserted LTRs at various locations within a plasmid containing the entire c-myc locus and cellular flanking sequences. To quantitatively measure effects on transcription, the Renilla luciferase gene was substituted for most of c-myc exon 2, and transient transfections were performed with c-myc reporter constructs in two different T-cell lines. As expected, insertion of a TBLV LTR with three-repeat enhancers in either orientation, 5" and 3", of the myc gene elevated reporter activity from 2- to 160-fold, consistent with enhancer function, but four-repeat LTRs had lower levels of expression compared to three-repeat LTRs. Surprisingly, LTR insertions that gave maximal c-myc expression in transient-transfection assays declined in tumor cells selected for growth in vivo. Selection for clonal growth may occur in tumor cells that have modest c-myc overexpression after proviral insertion to prevent apoptosis.

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