title: Neoplastic transformation of T lymphocytes through transgenic expression of a virus host modification protein.
abstract: Virus host evasion genes are ready-made tools for gene manipulation and therapy. In this work we have assessed the impact in vivo of the evasion gene A238L of the African Swine Fever Virus, a gene which inhibits transcription mediated by both NF-κB and NFAT. The A238L gene has been selectively expressed in mouse T lymphocytes using tissue specific promoter, enhancer and locus control region sequences for CD2. The resulting two independently derived transgenic mice expressed the transgene and developed a metastasic, angiogenic and transplantable CD4(+)CD8(+)CD69(-) lymphoma. The CD4(+)CD8(+)CD69(-) cells also grew vigorously in vitro. The absence of CD69 from the tumour cells suggests that they were derived from T cells at a stage prior to positive selection. In contrast, transgenic mice similarly expressing a mutant A238L, solely inhibiting transcription mediated by NF-κB, were indistinguishable from wild type mice. Expression of Rag1, Rag2, TCRβ-V8.2, CD25, FoxP3, Bcl3, Bcl2 l14, Myc, IL-2, NFAT1 and Itk, by purified CD4(+)CD8(+)CD69(-) thymocytes from A238L transgenic mice was consistent with the phenotype. Similarly evaluated expression profiles of CD4(+)CD8(+) CD69(-) thymocytes from the mutant A238L transgenic mice were comparable to those of wild type mice. These features, together with the demonstration of (mono-)oligoclonality, suggest a transgene-NFAT-dependent transformation yielding a lymphoma with a phenotype reminiscent of some acute lymphoblastic lymphomas.
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal. scpalmeida@gmail.com
authors.forename: Sílvia Cristina Paiva
authors.initials: SC
authors.lastname: Almeida
authors.forename: Vivian Leite
authors.initials: VL
authors.lastname: de Oliveira
authors.forename: Sónia
authors.initials: S
authors.lastname: Ventura
authors.forename: Margarita
authors.initials: M
authors.lastname: Bofill
authors.forename: Robert Michael Evans
authors.initials: RM
authors.lastname: Parkhouse
mesh_terms: D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018628:Gene Dosage; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D006652:Histological Techniques; D008223:Lymphoma / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000503:physiopathology / Q000821:virology; D010957:Plasmids / Q000235:genetics; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000473:pathology* / Q000821:virology; D060168:Thymocytes / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: C113585:A238L protein, African swine fever virus; D015704:CD4 Antigens; D016827:CD8 Antigens; D017931:DNA Primers; D050778:NFATC Transcription Factors; D014764:Viral Proteins