title: HTLV-1-infected CD4+ T-cells display alternative exon usages that culminate in adult T-cell leukemia.
abstract: BACKGROUND
  Reprogramming cellular gene transcription sustains HTLV-1 viral persistence that ultimately leads to the development of adult T-cell leukemia/lymphoma (ATLL). We hypothesized that besides these quantitative transcriptional effects, HTLV-1 qualitatively modifies the pattern of cellular gene expression.
  
  
  RESULTS
  Exon expression analysis shows that patients' untransformed and malignant HTLV-1(+) CD4(+) T-cells exhibit multiple alternate exon usage (AEU) events. These affect either transcriptionally modified or unmodified genes, culminate in ATLL, and unveil new functional pathways involved in cancer and cell cycle. Unsupervised hierarchical clustering of array data permitted to isolate exon expression patterns of 3977 exons that discriminate uninfected, infected, and transformed CD4(+) T-cells. Furthermore, untransformed infected CD4+ clones and ATLL samples shared 486 exon modifications distributed in 320 genes, thereby indicating a role of AEUs in HTLV-1 leukemogenesis. Exposing cells to splicing modulators revealed that Sudemycin E reduces cell viability of HTLV-1 transformed cells without affecting primary control CD4+ cells and HTLV-1 negative cell lines, suggesting that the huge excess of AEU might provide news targets for treating ATLL.
  
  
  CONCLUSIONS
  Taken together, these data reveal that HTLV-1 significantly modifies the structure of cellular transcripts and unmask new putative leukemogenic pathways and possible therapeutic targets.
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. morgan.thenoz@ens-lyon.fr.
authors.forename: Morgan
authors.initials: M
authors.lastname: Thénoz
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. celine.vernin@gmail.com.
authors.forename: Céline
authors.initials: C
authors.lastname: Vernin
authors.affiliation: Centre de Recherche sur le Cancer de Lyon, France Epissage alternatif et progression tumorale, Lyon, France. hussein.mortada@inserm.fr.
authors.forename: Hussein
authors.initials: H
authors.lastname: Mortada
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. maroun-karam@hotmail.fr.
authors.forename: Maroun
authors.initials: M
authors.lastname: Karam
authors.affiliation: Centre de Recherche sur le Cancer de Lyon, France Epissage alternatif et progression tumorale, Lyon, France. christiane.pinatel@lyon.unicancer.fr.
authors.forename: Christiane
authors.initials: C
authors.lastname: Pinatel
authors.affiliation: Institut Pasteur, Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Paris, France. agessain@pasteur.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Gessain
authors.affiliation: SRI International, 333 Ravenswood Avenue, Menlo Park, CA, 94025-3493, USA. thomas.webb@sri.com.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
authors.affiliation: Centre de Recherche sur le Cancer de Lyon, France Epissage alternatif et progression tumorale, Lyon, France. Didier.auboeuf@inserm.fr.
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
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. eric.wattel@ens-lyon.fr.|Université Lyon I, Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France. eric.wattel@ens-lyon.fr.|Oncovirologie et Biotherapies, Laboratoire de Biologie Moléculaire de la Cellule, UMR5239 CNRS/ENS, Lyon/UCBL/HCL; Ecole normale supérieure de Lyon, 46, allée d'Italie; 69364, Lyon cedex 07, France. eric.wattel@ens-lyon.fr.
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.|Oncovirologie et Biotherapies, Laboratoire de Biologie Moléculaire de la Cellule, UMR5239 CNRS/ENS, Lyon/UCBL/HCL; Ecole normale supérieure de Lyon, 46, allée d'Italie; 69364, Lyon cedex 07, France. franck.mortreux@ens-lyon.fr.
authors.forename: Franck
authors.initials: F
authors.lastname: Mortreux
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D005091:Exons; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D014158:Transcription, Genetic