Viral integration near c-myc in 10-20% of mcf 247-induced AKR lymphomas.

Li, Yen; Holland, Christie A.; Hartley, Janet W.; Hopkins, Nancy

doi:10.1073/pnas.81.21.6808

Cited by 129 publications

(78 citation statements)

References 30 publications

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“…1. Most (32 of 40) of the proviral integrations were in the reverse transcriptional orientation to c-myc and were distributed about a median distance 0.7-kilobase (kb) 5' of exon 1, a finding similar to that reported by other workers (3,9,19). Of the eight tumors with colinear proviral integrations, only two of them, with insertions at +0.7 kb and +5.2 kb, were available for analysis in this study.…”

supporting

confidence: 80%

Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice.

Reicin¹,

Yang²,

Marcu³

et al. 1986

Mol. Cell. Biol.

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A high frequency (.65%) of thymomas induced by mink cell focus-forming virus 69L1 in AKR/J mice contain proviral integrations which are clustered 0.7-kilobase upstream of the c-myc oncogene predominantly in the opposite transcriptional orientation. Blot hybridization experiments showed that on the average there was only a twofold elevation of steady-state c-myc RNA in the thymomas as compared with levels in normal AKR/J thymocytes. Such an increase would not appear to be sufficient as a mechanism of oncogene activation in this system. In contrast, Si nuclease analysis of transcripts initiated from the two known c-myc promoters indicated a strong shift in promoter usage in virtually all thymomas tested. In normal thymus the ratio of transcripts initiated from the proximal promoter P1 to the distal promoter P2 was 0.2 to 0.3. In contrast, most of the thymomas tested (18 of 23) showed an average P1/P2 ratio of 1.2 regardless of whether or not proviral integrations could be detected within a 21-kilobase EcoRI fragment containing the three c-myc exons. We conclude that alterations in P1/P2 ratios are good indicators of c-myc deregulation in thymic lymphomas.The c-myc oncogene has been implicated in a variety of malignant neoplasms. In lymphoid tumors of both B-and T-cell lineages activation of c-myc has been associated with DNA rearrangements at the c-myc locus caused by either chromosomal translocations or retrovirus insertions (for-a recent review, see reference 25). Recently, we reported murine leukemia virus proviral integrations into the c-myc locus in 65% of thymic lymphomas induced by intrathymic injection of mink cell focus-forming virus (MCF) 69L1 into 40-day-old AKR/J mice (13). In this report we measured steady-state levels of both total c-myc RNA and c-myc transcripts initiated from each of the two known promoters of the gene to study the effect of proviral integration on expression of the c-myc oncogene. We present evidence that expression of c-myc is not increased markedly in MCFinduced thymomas but is deregulated in tumors as evidenced by a reversal of normal promoter usage. Altered levels of the two c-myc transcripts also were observed in many instances in which a proviral integration was not detected near c-myc.A map of MCF proviral integration sites for 40 independent primary thymomas which have been analyzed to date is shown in Fig. 1. Most (32 of 40) of the proviral integrations were in the reverse transcriptional orientation to c-myc and were distributed about a median distance 0.7-kilobase (kb) 5' of exon 1, a finding similar to that reported by other workers (3,9,19). Of the eight tumors with colinear proviral integrations, only two of them, with insertions at +0.7 kb and +5.2 kb, were available for analysis in this study.Steady-state levels of c-myc RNA were measured by slot-blot analysis of total cellular RNA (Fig. 2a). Samples of total RNA (2) in 4.6 M formaldehyde-7.5 x SSC (0.1 M sodium chloride, 0.01 M sodium citrate) were heated at 65°C for 15 min, diluted serially, and applied to two se...

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supporting

confidence: 80%

Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice.

Reicin¹,

Yang²,

Marcu³

et al. 1986

Mol. Cell. Biol.

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“…Sequencing of the 1.5-kb region containing the c-myc breaktomas (58) and is also the site of proviral insertion in murine point cluster reveals several regions of homology between the T-cell lymphomas (7,25,44,57) and in Moloney-virusrat, mouse, and human sequences. The breakpoint localizainduced rat thymomas (52).…”

Section: Methodsmentioning

confidence: 99%

6;7 chromosomal translocation in spontaneously arising rat immunocytomas: evidence for c-myc breakpoint clustering and correlation between isotypic expression and the c-myc target.

Pear¹,

Wahlström²,

Nelson³

et al. 1988

Mol. Cell. Biol.

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Our previous studies have shown that spontaneously arising immunocytomas in the LOU/Wsl strain of rats contain a t(6;7) chromosomal translocation in all seven tumors studied (F. Wiener, M. Babonits, J. Spira, G. Klein, and H. Bazin, Int. J. Cancer 29:431-437, 1982). We have also shown that the c-myc is located on chromosome 7 (J. Sumegi, J. Spira, H. Bazin, J. Szpirer, G. Levan, and G. Klein, Nature (London) 306: [497][498][499] 1983) and the immunoglobulin H cluster on chromosome 6 (W. S. Pear, G. Wahistrom, J. Szpirer, G. Levan, G. Klein, and J. Sumegi, Immunogenetics 23:393-395, 1986). We now report a detailed cytogenetic and molecular analysis of nine additional rat immunocytomas. The t(6;7) chromosomal translocation is found in all tumors. Mapping of the c-myc breakpoints showed that in 10 of 14 tumors, the c-myc breakpoints are clustered in a 1.5-kilobase region upstream of exon 1. In contrast with sporadic Burkitt's lymphoma and mouse plasmacytoma, only 1 of 14 tumors contains the c-myc breakpoints in either exon 1 or intron 1. Analysis of the sequences juxtaposed to the c-myc show that immunoglobulin H switch regions are the targets in at least five tumors and that there is a strong correlation between the secreted immunoglobulin and the c-myc target. Unlike sporadic Burkitt's lymphoma and mouse plasmacytoma, at least two rat immunocytomas show recombination of the c-myc with sequences distinct from immunoglobulin switch regions.Consistent chromosomal translocations are thought to play an important role in the development of certain neoplasms (10, 21). The role of specific translocations has been extensively studied in two B-cell tumors, Burkitt's lymphoma (BL) and mouse plasmacytoma (MPC), and chromosomal translocations have been identified in 100% of the former and 95% of the latter type of tumor (22). BL and MPC represent different stages of B-cell maturation; however, the chromosome translocation in both tumors involves the chromosomes containing one of the immunoglobulin loci and the c-myc cellular oncogene (23). The translocation is believed to act by constitutive activation of c-myc (9). Recent facsimile experiments have shown that constitutively activated c-myc genes can induce tumors in an appropriate host environment (1,24,27

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“…Since the provirus appeared to have inserted into an intron sequence, the presence of both splice donor and acceptor sites in the vector could have led to alternative splicing and loss of hprt expression as has been previously shown for the dilute mutation. 4 Alternatively, loss of gene expression may have been caused by viral transcription in the opposite orientation to transcription of the hprt gene by the LHL virus, which has also been shown previously to interfere with c-myc oncogene expression, 22 or for the remaining mutants not examined here, provirus insertion(s) within putative hprt promoter/enhancer regions outside the hprt locus may have occurred. Several novel Retrovirus insertional mutagenesis of V79 cells M Themis et al DNA fragments also identified by Southern analysis in coculture-infected mutants using the hprt cDNA probe may have been the result of recombination events between integrated LHL proviruses.…”

Section: à5mentioning

confidence: 66%

Mutational effects of retrovirus insertion on the genome of V79 cells by an attenuated retrovirus vector: implications for gene therapy

et al. 2003

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Attenuated retroviruses are currently the most widely used vectors in clinical gene therapy because of their potential to effect stable and permanent gene transfer. Since gene delivery is accompanied by random insertion of foreign genetic material into the recipient chromosomal DNA, the potential for insertional mutagenesis exists. In this study, we used a defective retrovirus vector containing a selectable marker, the hygromycin phosphotransferase gene, to investigate the mutagenic effects of vector integration on the mammalian genome. V79 Chinese hamster cells were infected with virus supernatants or by coculture with virus producer cells, and provirus insertion events occurred at low and high frequencies, respectively. The frequency of hprt mutagenesis was increased by a factor of 2.3 over the spontaneous hprt mutation frequency only following multiple provirus insertions/cell genome. Multiple provirus insertions (43/genome) resulted in instability at the hprt locus in 63% of the virally induced hprt mutants, as indicated by rearrangements at the molecular level, whereas no rearrangements were found when the provirus copy number was 1-2/genome. To demonstrate direct proviral involvement in mutagenesis, the defective MLV vector was retrieved along with flanking genomic hprt sequences from one mutant, and localized within intron 5 of the hprt gene. These data suggest that provirus copy number is a key factor when considering the potential hazards of using retrovirus vectors for gene therapy.

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Viral integration near c-myc in 10-20% of mcf 247-induced AKR lymphomas.

Cited by 129 publications

References 30 publications

Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice.

Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice.

6;7 chromosomal translocation in spontaneously arising rat immunocytomas: evidence for c-myc breakpoint clustering and correlation between isotypic expression and the c-myc target.

Mutational effects of retrovirus insertion on the genome of V79 cells by an attenuated retrovirus vector: implications for gene therapy

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