Somatic Mutation in Human T-Cell Leukemia Virus Type 1 Provirus and Flanking Cellular Sequences During Clonal Expansion In Vivo
| العنوان: | Somatic Mutation in Human T-Cell Leukemia Virus Type 1 Provirus and Flanking Cellular Sequences During Clonal Expansion In Vivo |
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| المؤلفون: | Anne-Sophie Gabet, Antoine Gessain, Arnaud Leroy, Eric Wattel, India Leclercq, Simon Wain-Hobson, Eric Westhof, Franck Mortreux |
| المساهمون: | Unite d'Oncogenese Virale, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Génétique moléculaire et approches thérapeutiques des hémopathies malignes, IRCL-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Rétrovirologie Moléculaire, Institut Pasteur [Paris], Supported by grants from the Association pour la Recherche sur le Cancer, from the Fondation Contre la Leuce´mie, and from the Comite´ De´partemental du Rhoˆne de la Ligue Nationale Contre le Cancer. I. Leclercq and F. Mortreux were supported by bursaries from the Ministe`re de l'Enseignement Supe´rieur et de la Recherche. A.-S. Gabet was supported by a grant from the Centre Le´on Berard., Université de Lille-UNICANCER-Université de Lille-UNICANCER, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP) |
| المصدر: | JNCI: Journal of the National Cancer Institute JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), 2001, 93 (5), pp.367-77. ⟨10.1093/jnci/93.5.367⟩ JNCI: Journal of the National Cancer Institute, 2001, 93 (5), pp.367-77. ⟨10.1093/jnci/93.5.367⟩ |
| بيانات النشر: | Oxford University Press (OUP), 2001. |
| سنة النشر: | 2001 |
| مصطلحات موضوعية: | Cancer Research, Viral/genetics, Transcription, Genetic, Polymerase Chain Reaction/methods, Somatic cell, Genetic/*genetics, MESH: Base Sequence, medicine.disease_cause, Polymerase Chain Reaction, MESH: Proviruses, 0302 clinical medicine, Proviruses, Proviruses/*genetics, MESH: Blotting, Southern, Cloning, Molecular, Non-U.S. Gov't, OCIS 000.1430, Southern, Genetics, Human T-lymphotropic virus 1, 0303 health sciences, Blotting, Inverse polymerase chain reaction, Provirus, 3. Good health, Blotting, Southern, Human T-lymphotropic virus 1/*genetics, MESH: Terminal Repeat Sequences, Oncology, MESH: RNA, Viral, 030220 oncology & carcinogenesis, Viral/*genetics, Terminal Repeat Sequences/*genetics, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, Transcription, Adult, MESH: DNA Primers, MESH: Mutation, Molecular Sequence Data, Biology, Research Support, MESH: Phosphopyruvate Hydratase, Virus, 03 medical and health sciences, Germline mutation, medicine, Humans, MESH: Cloning, Molecular, DNA Primers, 030304 developmental biology, MESH: Human T-lymphotropic virus 1, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Transcription, Genetic, Terminal Repeat Sequences, Molecular, MESH: Adult, MESH: Polymerase Chain Reaction, DNA, biology.organism_classification, Virology, Reverse transcriptase, MESH: DNA, Viral, Phosphopyruvate Hydratase, DNA, Viral, Mutation, RNA, Phosphopyruvate Hydratase/genetics, Carcinogenesis, Cloning |
| الوصف: | International audience; BACKGROUND:Human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma, shows intrapatient genetic variability. Although HTLV-1 can replicate via the reverse transcription of virion RNA to a double-stranded DNA provirus (the conventional manner for retroviruses), its predominant mode of replication is via the clonal expansion (mitosis) of the infected cell. This expansion is achieved by the viral oncoprotein Tax, which keeps the infected CD4 T lymphocyte cycling. Because Tax also interferes with cellular DNA repair pathways, we investigated whether somatic mutations of the provirus that occur during the division of infected cells could account for HTLV-1 genetic variability.METHODS:An inverse polymerase chain reaction strategy was designed to distinguish somatic mutations from reverse transcription-associated substitutions. This strategy allows the proviral sequences to be isolated together with flanking cellular sequences. Using this method, we sequenced 208 HTLV-1 provirus 3' segments, together with their integration sites, belonging to 29 distinct circulating cellular clones from infected individuals.RESULTS:For 60% of the clones, 8%-80% of infected cells harbored a mutated HTLV-1 provirus, without evidence of reverse transcription-associated mutations. Mutations within flanking cellular sequences were also identified at a frequency of 2.8 x 10(-4) substitution per base pair. Some of these clones carried multiple discrete substitutions or deletions, indicating progressive accumulation of mutations during clonal expansion. The overall frequency of somatic mutations increased with the degree of proliferation of infected T cells.CONCLUSIONS:These data indicate that, in vivo, HTLV-1 variation results mainly from postintegration events that consist of somatic mutations of the proviral sequence occurring during clonal expansion. The finding of substitutions in flanking sequences suggests that somatic mutations occurring after integration, presumably coupled with selection, help move the cellular clones toward a transformed phenotype, of which adult T-cell leukemia/lymphoma is the end point. |
| تدمد: | 1460-2105 0027-8874 |
| DOI: | 10.1093/jnci/93.5.367 |
| DOI: | 10.1093/jnci/93.5.367⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::38927e8327e7e892de0e871911b8c827 https://doi.org/10.1093/jnci/93.5.367 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....38927e8327e7e892de0e871911b8c827 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602105 00278874 |
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| DOI: | 10.1093/jnci/93.5.367 |