Neoplastic Transformation of T Lymphocytes through Transgenic Expression of a Virus Host Modification Protein

• Autor(a) principal: Almeida, Sílvia Cristina Paiva
• Data de Publicação: 2012
• Outros Autores: de Oliveira, Vivian Leite, Ventura, Sónia, Bofill, Margarita, Parkhouse, Robert Michael Evans
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.7/659
• topic: Animals; Antigens, CD4; Antigens, CD8; Base Sequence; Blotting, Southern; Cell Transformation, Neoplastic; DNA Primers; Flow Cytometry; Fluorescent Antibody Technique; Gene Dosage; Gene Expression Profiling; Histological Techniques; Lymphoma; Mice; Mice, Transgenic; Molecular Sequence Data; NFATC Transcription Factors; Neovascularization, Pathologic; Plasmids; Sequence Analysis, DNA; T-Lymphocytes; Thymocytes; Viral Proteins; Gene Transfer Techniques

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.