title: HTLV-1 bZIP factor HBZ promotes cell proliferation and genetic instability by activating OncomiRs.
abstract: Viruses disrupt the host cell microRNA (miRNA) network to facilitate their replication. Human T-cell leukemia virus type I (HTLV-1) replication relies on the clonal expansion of its host CD4(+) and CD8(+) T cells, yet this virus causes adult T-cell leukemia/lymphoma (ATLL) that typically has a CD4(+) phenotype. The viral oncoprotein Tax, which is rarely expressed in ATLL cells, has long been recognized for its involvement in tumor initiation by promoting cell proliferation, genetic instability, and miRNA dysregulation. Meanwhile, HBZ is expressed in both untransformed infected cells and ATLL cells and is involved in sustaining cell proliferation and silencing virus expression. Here, we show that an HBZ-miRNA axis promotes cell proliferation and genetic instability, as indicated by comet assays that showed increased numbers of DNA-strand breaks. Expression profiling of miRNA revealed that infected CD4(+) cells, but not CD8(+) T cells, overexpressed oncogenic miRNAs, including miR17 and miR21. HBZ activated these miRNAs via a posttranscriptional mechanism. These effects were alleviated by knocking down miR21 or miR17 and by ectopic expression of OBFC2A, a DNA-damage factor that is downregulated by miR17 and miR21 in HTLV-1-infected CD4(+) T cells. These findings extend the oncogenic potential of HBZ and suggest that viral expression might be involved in the remarkable genetic instability of ATLL cells.
authors.affiliation: Université de Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Laboratoire de Biologie Moléculaire de la Cellule, Faculté de Médecine Lyon Sud, Pierre Bénite, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Vernin
authors.affiliation: Université de Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Laboratoire de Biologie Moléculaire de la Cellule, Faculté de Médecine Lyon Sud, Pierre Bénite, France.
authors.forename: Morgan
authors.initials: M
authors.lastname: Thenoz
authors.affiliation: Centre de Recherche sur le Cancer de Lyon, Centre Léon Bérard, Lyon, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Pinatel
authors.affiliation: Institut Pasteur, Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Gessain
authors.affiliation: Fondation Rothschild, Service de Neurologie, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gout
authors.affiliation: CHU Henri Mondor, Laboratoire d'Immunologie, Créteil, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Delfau-Larue
authors.affiliation: Université Lyon I, Faculté de Médecine et de Pharmacie de Lyon, ISPBL Viroscan3D-Profilexpert, UMR5557, Ecologie Microbienne, Lyon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nazaret
authors.affiliation: Université Lyon I, Faculté de Médecine et de Pharmacie de Lyon, ISPBL Viroscan3D-Profilexpert, UMR5557, Ecologie Microbienne, Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Legras-Lachuer
authors.affiliation: Université de Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Laboratoire de Biologie Moléculaire de la Cellule, Faculté de Médecine Lyon Sud, Pierre Bénite, France. Université Lyon I, Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Wattel
authors.affiliation: Université de Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Laboratoire de Biologie Moléculaire de la Cellule, Faculté de Médecine Lyon Sud, Pierre Bénite, France. franck.mortreux@ens-lyon.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Mortreux
mesh_terms: D000328:Adult; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D016355:Genes, pX / Q000235:genetics; D042822:Genomic Instability; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012191:Retroviridae Proteins; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; D014764:Viral Proteins