Murine leukemia virus proviral insertions between the N-ras and unr genes in B-cell lymphoma DNA affect the expression of N-ras only (original) (raw)
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Virology, 2007
This study investigates the role of the proviral transcriptional enhancer for B-lymphoma induction by exogenous Akv murine leukemia virus. Infection of newborn inbred NMRI mice with Akv induced 35% plasma cell proliferations (PCPs) (consistent with plasmacytoma), 33% diffuse large B-cell lymphomas, 25% follicular B-cell lymphomas and few splenic marginal zone and small B-cell lymphomas. Deleting one copy of the 99-bp proviral enhancer sequence still allowed induction of multiple B-cell tumor types, although PCPs dominated (77%). Additional mutation of binding sites for the glucocorticoid receptor, Ets, Runx, or basic helix-loop-helix transcription factors in the proviral U3 region, however, shifted disease induction to almost exclusively PCPs, but had no major influence on tumor latency periods. Southern analysis of immunoglobulin rearrangements and ecotropic provirus integration patterns showed that many of the tumors/cell proliferations induced by each virus were polyclonal. Our results indicate that enhancer mutations weaken the ability of Akv to induce mature B-cell lymphomas prior to the plasma cell stage, whereas development of plasma cell proliferations is less dependent of viral enhancer strength.
Virology, 2006
In a small sample of 57 retrovirus integration sites (RISs) isolated from 23 end-stage lymphomas induced in NMRI mice by the Blymphotropic Akv wt or an enhancer mutant hereof, Akv1-99, we identified 14 novel RISs and defined 9 novel CISs (common insertion sites). Moreover, when comparing with RISs from tumors induced by the T-lymphomagenic SL3-3, we observed that SL3-3 targets RefSeq promoter regions with a significantly higher frequency than Akv/Akv1-99 and in an orientation-dependent way. Altogether, our results strongly emphasize the importance of host genetic background and virus type for retroviral insertion mutagenesis screens and suggest that different types of MLV may favor specific genomic regions and orientations in order exert optimal effect on target gene expression during lymphoma induction and development.
Akv murine leukemia virus enhances lymphomagenesis in myc-kappa transgenic and in wild-type mice
Virology, 1995
The contribution of endogenous retroviruses to the multistep process of lymphomagenesis was investigated in wild-type mice and in two different myc-• transgenic mouse lines by infection with Akv. This retrovirus is derived from the endogenous ecotropic provirus of the AKR mouse and was previously considered to be nonlymphomagenic. The mice of the two myck transgenic lines are predisposed to B-cell lymphomagenesis and were therefore considered to be more susceptible to Akv. For comparison, the same mouse strains were also infected with the exogenous Moloney murine leukemia virus (MoMuLV). Both MoMuLV and Akv increased the tumor incidence and shortened the tumor latency period in wild-type mice and in the transgenic mouse lines. The differences in pathogenicity, number of provirus integrations, and level of virus expression between MoMuLV and Akv indicate different mechanisms of lymphomagenesis: while MoMuLV induced tumors apparently by insertional mutagenesis involving common integration sites similar to previous reports, the enhancement of lymphomagenesis by Akv seems to be directed by other mechanisms.
Journal of virology, 1991
The Cas-Br-E murine leukemia virus is a nondefective retrovirus that induces non-T-, non-B-cell lymphomas in susceptible NIH/Swiss mice. By using a DNA probe derived from Cas-Br-E provirus-flanking sequences, we identified a DNA region, originally called Sic-1, rearranged in 16 of 24 tumors analyzed (67%). All proviruses were integrated in a DNA segment smaller than 100 bp and were in the same 5'-to-3' orientation. Ecotropic as well as mink cell focus-forming virus types were found integrated in that specific DNA region. On the basis of Southern blot analysis of somatic cell hybrids and progeny of an interspecies backcross, the Sic-1 region was localized on mouse chromosome 9 near the previously described proto-oncogenes or common viral integration sites: Ets-1, Cbl-2, Tpl-1, and Fli-1. Restriction map analysis shows that this region is identical to the Fli-1 locus identified in Friend murine leukemia virus-induced erythroleukemia cell lines and thus may contain sequences al...
Journal of virology, 1986
Structures of somatically acquired murine leukemia virus (MuLV) genomes present in the DNA of a large panel of MuLV-induced C57BL and BALB/c B and non-T/non-B cell lymphomas were compared with those present in MuLV-induced T-cell lymphomas induced in the same low-"spontaneous"-lymphoma-incidence mice. Analyses were performed with probes specific for the gp70, p15E, and U3-long terminal repeat (LTR) regions of ecotropic AKV MuLV and a mink cell focus-forming virus (MCF)-LTR probe annealing with U3-LTR sequences of a unique endogenous xenotropic MuLV, which also hybridizes with U3-LTR sequences of a substantial portion of somatically acquired MCF genomes in spontaneous AKR thymomas. The DNAs of both T- and B-cell tumors induced by neonatal inoculation with the highly oncogenic C57BL-derived MCF 1233 virus predominantly contain integrated MCF proviruses. In contrast, the DNAs of more slowly developing B and non-T/non-B cell lymphomas induced by poorly oncogenic ecotropic or M...
Distinct chromosomal abnormalities in murine leukemia virus-induced T- and B-cell lymphomas
International Journal of Cancer, 1989
We performed a cytogenetic study on 16 murine mature B-cell lymphomas and 10 T-cell lymphomas, using G-banding techniques. All tumors, with the exception of 3 spontaneous 6-cell tumors, were induced by various slowly transforming murine leukemia viruses (MuLV). Metaphases were obtained from primary (10 6-cell tumors) and first or second transplant generation lymphomas (6 6-cell and 10 T-cell tumors), all of which were well characterized with respect to phenotypic, histologic and genotypic features. In the T-cell tumors we found relatively simple karyotypic abnormalities, including various numerical aberrations, such as trisomy 15, in line with many earlier reports. However, the majority of 6-cell tumors showed a great variety of both structural and numerical chromosomal anomalies. Three 6-cell lymphomas had an apparently normal karyotype. No single cytogenetic abnormality occurred commonly in the 6-cell lymphomas, but some structural abnormalities were found in more than one stemline, in particular, ins (I I) (Al; A2) in 3 tumors, and deletions involving the D-region of chromosome 14 in 3 other lymphomas. These cytogenetic results clearly indicate that the pathogenic mechanisms involved in MuLV-induced (long latency) 6-cell lymphomagenesis and (short latency) T-cell lymphomagenesis differ considerably. MATERIAL AND METHODS Mice, viruses and lymphomas Primary lymphomas were induced by injection of newborn C57BL or BALB/c mice with various MuLV strains (Zijlstra et al., 1984; Vasmel et al., 1988). Spontaneously developing lymphomas and lymphomas induced by a milk-transmitted Btropic ecotropic MuLV were obtained as reported (Melief et ~ 3 T~ whom reprint requests should be addressed.
Cell, 1984
A number of mink cell focus-forming (MCF) proviruses was molecularly cloned from mouse lymphoma DNA. From each clone, flanking probes were prepared to detect common integration regions in other MuLV-induced lymphomas. One clone frequently revealed variations in the molecular structure of the corresponding region (Pim-1) in other lymphomas. The results show the following. Changes in the Pim region are seen in 24 out of 93 lymphomas tested. Over 50% of the early T-cell lymphomas show integration in the Pim-1 region. The alterations are seen in different mouse strains and with various MuLVs. The observed variations are caused by the integration of predominantly MCF genomes. All integrations occur in a region spanning less than 20 kb and are associated with the transcriptional activation of a distinct region within the Pim-1 domain. The activated region does not show any homology with 13 known and three putative oncogenes.
Ror (Rorc) Is a Common Integration Site in Type B Leukemogenic Virus-Induced T-Cell Lymphomas
Journal of Virology, 2004
The retrovirus type B leukemogenic virus (TBLV) causes T-cell lymphomas in mice. We have identified the Ror␥ locus as an integration site in 19% of TBLV-induced tumors. Overexpression of one or more Ror␥ isoforms in >77% of the tumors tested may complement apoptotic effects of c-myc overexpression. Type B leukemogenic virus (TBLV) is a retrovirus that is more than 98% identical to mouse mammary tumor virus (MMTV) (1, 7). Differences between MMTV and TBLV include a 440-bp deletion of U3 sequences present within the MMTV long terminal repeat (LTR). This deletion removes negative regulatory elements that inhibit viral transcription in many cell types, including lymphoid cells. LTR sequences flanking the deletion also are triplicated in the TBLV U3 region to form a T-cell-specific enhancer (24). Our previous results have shown that cis-acting sequences from the TBLV LTR are sufficient to convert the disease tropism of an infectious MMTV provirus from relatively long latency mammary tumors (6 to 9 months) to rapidly appearing T-cell lymphomas (2 to 3 months) (2). Retroviruses that lack encoded oncogenes appear to induce cancer by insertional mutagenesis, leading to deregulation of nearby genes. Because retroviral integration is relatively random, identification of viral insertions within or near the same genes in different tumors suggests that there has been selection for outgrowth of cells carrying specific insertions. Such common integration sites (CISs) have been used as molecular tags to identify oncogenes, tumor suppressor genes, and oncogenic pathways (5, 12, 17, 19, 25, 31). There are at least nine MMTV CISs, which generally fall into three categories (Wnt, Fgf, and Notch family genes [4, 16, 20, 21, 33]), whereas only two CISs, Tblvi1 and c-myc, have been described for TBLV. The Tblvi1 CIS was identified in 20% of 55 TBLV-induced T-cell lymphomas examined (26) and mapped to the mouse X chromosome, but the target gene(s) remains unknown. We have detected integrations within or near the c-myc locus in 23% of TBLVinduced tumors (references 3 and 28 and data not shown). However, unlike many other murine retroviral studies, our previous analysis of 35 TBLV-induced tumors revealed only two tumors with detectable c-myc arrangement by Southern analysis, while PCR analysis confirmed that those two tumors plus nine others had TBLV integrations near or within this locus (3). Surprisingly, one tumor (T623B) had at least seven TBLV insertions at four sites within or near the c-myc locus. These studies suggested that TBLV-induced lymphomas are
Journal of Virology, 1981
A specific cDNA probe of AKR murine leukemia virus (AKR-MLV) was prepared to detect AKR-MLV sequences in normal and tumor tissues in a variety of AKR mouse substrains. AKR strains contained up to six endogenous AKR-MLV genomes. All substrains tested had one AKR-MLV locus in common, and closely related substrains had several proviruses integrated in an identical site. Virus-induced tumors in the AKR/FuRdA and AKR/JS strains showed a reintegration pattern of AKR-MLV sequences unique for the individual animal, suggesting a monoclonal origin for the outgrown tumors. An analysis of tumor DNAs from the AKR/FuRdA and AKR/JS substrains with restriction enzymes cleaving within the proviral genome revealed a new EcoRI restriction site and BamHI restriction site not present in normal tissues. The positions of these sites corresponded both with cleavage sites of EcoRI and BamHI in integrated Moloney recombinants and with the structure of isolated AKR mink cell focus-forming viruses. All tumors ...