The tandem direct repeats within the long terminal repeat of murine leukemia viruses are the primary determinant of their leukemogenic potential

DesGroseillers, Luc; Jolicoeur, Paul

doi:10.1128/jvi.52.3.945-952.1984

Cited by 145 publications

(66 citation statements)

References 42 publications

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“…We have previously observed that MMTV structural proteins expressed in BALB/cf/Cd kidney tumor cells are identical in size and antigenicity to the viral polypeptides synthesized in mammary tumor cells (M.Garcia, R.Wellinger, A.Vessaz and H.Digglemann, in preparation). Subtle changes in the protein coding sequences and/or in the viral LTR, however, might allow MMTV to acquire a new host range, as has been proposed for other virus systems (Celander and Haseltine, 1984;Desgroseillers and Jolicoeur, 1984;Gonda et al, 1984;Oliff et al, 1985).…”

Section: Discussionmentioning

confidence: 97%

A new site of integration for mouse mammary tumor virus proviral DNA common to BALB/cf(C3H) mammary and kidney adenocarcinomas.

Garcia¹,

Wellinger²,

Vessaz³

et al. 1986

The EMBO Journal

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The BALB/cf/Cd substrain of mice, developed by inbreeding and selection, shows a 70% incidence of spontaneous kidney adenocarcinomas. Initially foster‐nursed on C3H mothers, these mice no longer produce mammary tumors, but there is evidence that mouse mammary tumor virus (MMTV) is involved in the formation of these renal carcinomas. We identified a chromosomal region called int‐41, representing a locus interrupted by the integration of an exogenous MMTV provirus in a BALB/c mammary tumor. We found a DNA rearrangement and transcriptional activation in the domain specified by the int‐41 probe in one primary kidney adenocarcinoma. A 5.2‐kb int‐41 specific mRNA was detected in the kidney tumor cell line established from a transplantable renal adenocarcinoma. This mRNA hybridized with MMTV and int‐41 specific probes suggesting that it is a hybrid molecule composed of MMTV‐LTR sequences covalently linked to host cell RNA. This mRNA was strongly stimulated by the presence of glucocorticoid hormone in the culture medium. Our data are compatible with the hypothesis that the int‐41 chromosomal domain is involved in the neoplastic transformation of epithelial cells from different organs.

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Section: Discussionmentioning

confidence: 97%

A new site of integration for mouse mammary tumor virus proviral DNA common to BALB/cf(C3H) mammary and kidney adenocarcinomas.

Garcia¹,

Wellinger²,

Vessaz³

et al. 1986

The EMBO Journal

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“…MLV-induced leukemogenesis is a multistep process thought to involve deregulation of the expression of cellular protooncogenes by insertional mutagenesis (67,68). Numerous studies have shown that the retroviral enhancer in the U3 region is a major determinant of the latency and specificity of hematopoietic disease induction (8,14,22,30,33,55,59). A likely explanation for this is that a powerful enhancer in a given cell type, besides conferring a high replication rate, may allow the retrovirus to act as a strong insertional activator in that cell type (50,53).…”

mentioning

confidence: 99%

Second-site proviral enhancer alterations in lymphomas induced by enhancer mutants of SL3-3 murine leukemia virus: negative effect of nuclear factor 1 binding site

Ethelberg

Hållberg

Lovmand

et al. 1997

J Virol

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SL3-3 is a highly T-lymphomagenic murine retrovirus. Previously, mutation of binding sites in the U3 repeat region for the AML1 transcription factor family (also known as core binding factor [CBF], polyomavirus enhancer binding protein 2 [PEBP2], and SL3-3 enhancer factor 1 [SEF1]) were found to strongly reduce the pathogenicity of SL3-3 (B. Hallberg, J. Schmidt, A. Luz, F. S. Pedersen, and T. Grundström, J. Virol. 65:4177-4181, 1991). We have now examined the few cases in which tumors developed harboring proviruses that besides the AML1 (core) site mutations carried second-site alterations in their U3 repeat structures. In three distinct cases we observed the same type of alteration which involved deletions of regions known to contain binding sites for nuclear factor 1 (NF1) and the addition of extra enhancer repeat elements. In transient-expression experiments in T-lymphoid cells, these new U3 regions acted as stronger enhancers than the U3 regions of the original viruses.This suggests that the altered proviruses represent more-pathogenic variants selected for in the process of tumor formation. To analyze the proviral alterations, we generated a series of different enhancer-promoter reporter constructs. These constructs showed that the additional repeat elements are not critical for enhancer strength, whereas the NF1 sites down-regulate the level of transcription in T-lymphoid cells whether or not the AML1 (core) sites are functional. We therefore also tested SL3-3 viruses with mutated NF1 sites. These viruses have unimpaired pathogenic properties and thereby distinguish SL3-3 from Moloney murine leukemia virus.

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“…MLV-induced leukemogenesis is a complex process in which several regions in the viral genome participate (47,48). Of these, the transcriptional enhancer in the U3 region is a major determinant of the latency and specificity of hematopoietic disease induction (5,7,14,17,20,38,42).…”

mentioning

confidence: 99%

Increased lymphomagenicity and restored disease specificity of AML1 site (core) mutant SL3-3 murine leukemia virus by a second-site enhancer variant evolved in vivo

Ethelberg

Lovmand

Schmidt

et al. 1997

J Virol

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SL3-3 is a highly T-lymphomagenic murine retrovirus. The major genetic determinant of disease is the transcriptional enhancer, which consists of a repeated region with densely packed binding sites for several transcription factors, including AML1 (also known as core binding factor and polyoma enhancer-binding protein 2) and nuclear factor 1 (NF1). Previously, we examined the enhancer structure of proviruses from murine tumors induced by SL3-3 with mutated AML1 (core) sites and found a few cases of second-site alterations. These consisted of deletions involving the NF1 sites and alterations in overall number of repeat elements, and they conferred increased enhancer strength in transient transcription assays. We have now tested the pathogenicity of a virus harboring one such second-site variant enhancer in inbred NMRI mice. It induced lymphomas with a 100% incidence and a significantly shorter latency than the AML1 mutant it evolved from. The enhancer structure thus represents the selection for a more tumorigenic virus variant during the pathogenic process. Sequencing of provirus from the induced tumors showed the new enhancer variant to be genetically stable. Also, Southern blotting showed that the tumors induced by the variant were T-cell lymphomas, as were the wild-type-induced lymphomas. In contrast, tumors induced by the original core/AML1 site I-II mutant appeared to be of non-T-cell origin and several proviral genomes with altered enhancer regions could be found in the tumors. Moreover, reporter constructs with the new tumor-derived variant could not be transactivated by AML1 in cotransfection experiments as could the wild type. These results emphasize the importance of both core/AML1 site I and site II for the pathogenic potential of SL3-3 and at the same time show that second-site alterations can form a viral variant with a substantial pathogenic potential although both AML1 sites I and II are nonfunctional.

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The tandem direct repeats within the long terminal repeat of murine leukemia viruses are the primary determinant of their leukemogenic potential

Cited by 145 publications

References 42 publications

A new site of integration for mouse mammary tumor virus proviral DNA common to BALB/cf(C3H) mammary and kidney adenocarcinomas.

A new site of integration for mouse mammary tumor virus proviral DNA common to BALB/cf(C3H) mammary and kidney adenocarcinomas.

Second-site proviral enhancer alterations in lymphomas induced by enhancer mutants of SL3-3 murine leukemia virus: negative effect of nuclear factor 1 binding site

Increased lymphomagenicity and restored disease specificity of AML1 site (core) mutant SL3-3 murine leukemia virus by a second-site enhancer variant evolved in vivo

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