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Neoplastic Transformation of T Lymphocytes through Transgenic Expression of a Virus Host Modification Protein
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Orientador(es)
Resumo(s)
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.
Descrição
Palavras-chave
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
Contexto Educativo
Citação
Almeida SCP, de Oliveira VL, Ventura S, Bofill M, Parkhouse RME (2012) Neoplastic Transformation of T Lymphocytes through Transgenic Expression of a Virus Host Modification Protein. PLoS ONE 7(4): e34140. doi:10.1371/journal.pone.0034140
Editora
PLOS