Retrovirally induced murine B-cell tumors rarely show proviral integration in sites common in T-cell tumors (original) (raw)
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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
1994
The genetic basis of feline leukemia virus (FeLV)-induced lymphoma was investigated in a series of 63 lymphoid tumors and tumor cell lines of presumptive T-cell origin. These were examined for virus-induced rearrangements of the c-myc,flvi-2 (bmi-1),fit-1, and pim-1 loci, for T-cell receptor (TCR) gene rearrangements, and for the presence of env recombinant FeLV (FeLV-B). The myc locus was most frequently affected in naturally occurring lymphomas (32%; n = 38) either by transduction (21%) or by proviral insertion (11%). Proviral insertions were also common atflvi-2 (24%). The two other loci were occupied in a smaller number of the naturally occurring tumors (fit-i, 8%; pim-i, 5%). Examination of the entire set of tumors showed that significant numbers were affected at two (19%Yo) or three (5%) of the loci. Occupation of the fit-i locus was observed most frequently in tumors induced by FeLV-myc strains, whileflvi-2 insertions occurred with similar frequency in the presence or absence of obvious c-myc activation. These results suggest a hierarchy of mutational events in the genesis of feline T-cell lymphomas by FeLV and implicate insertion atfit-i as a late progression step. The strongest links observed were with T-cell development, as monitored by rearrangement status of the TCR n-chain gene, which was positively associated with activation of myc (P < 0.001), and with proviral insertion at flvi-2 (P = 0.02). This analysis also revealed a genetically distinct subset of thymic lymphomas with unrearranged TCR ,8-chain genes in which the known target loci were involved very infrequently. The presence of env recombinant FeLV (FeLV-B) showed a negative correlation with proviral insertion at fit-i, possibly due to the rapid onset of these tumors. These results shed further light on the multistep process of FeLV leukemogenesis and the relationships between lymphoid cell maturation and susceptibility to FeLV transformation.
Leukemia Research, 1990
Proto-oncogene transcriptional activation was analyzed in a group of MCF 247 MuLvinduced T-cell iymphomas to identify transformation-specific gene activations and determine whether the provirai insertion near a myc gene could promote a peculiar mechanism of transformation through a differential proto-oncogene expression pattern. Of the six lymphomas analyzed, three showed the MCF 247 provirus integrated within the N-myc locus, one carried the provirus integrated near c-myc, whereas for the remaining two, no evidence of proviral integrations in any of the known myc loci was obtained. Independently of the integrative events, the pattern of proto-oncogene expression was almost identical in all six lymphomas. These findings seem to rule out the existence of a peculiar pathway of transformation associated with the proviral insertion near a myc locus. Moreover, the transcription pattern observed was qualitatively identical to that displayed by normal thymocytes; only quantitative differences in c-or N-myc, c-myb and Ha-ras were observed. These results suggest that the T-cell proto-oncogene activation program is not qualitatively affected by the transforming event(s).
Journal of virology, 1986
Clonal selections occurring during the progression of Moloney murine leukemia virus (MuLV)-induced T-cell lymphomas in mice were examined in primary and transplanted tumors by monitoring various molecular markers: proviral integration patterns, MuLV insertions near c-myc and pim-1, and rearrangements of the immunoglobulin heavy chain and beta-chain T-cell receptor genes. The results were as follows. Moloney MuLV frequently induced oligoclonal tumors with proviral insertions near c-myc or pim-1 in the independent clones. Moloney MuLV acted as a highly efficient insertional mutagen, able to activate different (putative) oncogenes in one cell lineage. Clonal selections during tumor progression were frequently marked by the acquisition of new proviral integrations. Independent tumor cell clones exhibited a homing preference upon transplantation in syngeneic hosts and were differently affected by the route of transplantation.
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...