title: Telomeric damage in early stage of chronic lymphocytic leukemia correlates with shelterin dysregulation.
abstract: Cells of B-cell chronic lymphocytic leukemia (B-CLL) are characterized by short telomeres despite a low proliferative index. Because telomere length has been reported to be a valuable prognosis criteria, there is a great interest in a deep understanding of the origin and consequences of telomere dysfunction in this pathology. Cases of chromosome fusion involving extremely short telomeres have been reported at advanced stage. In the present study, we address the question of the existence of early telomere dysfunction during the B-CLL time course. In a series restricted to 23 newly diagnosed Binet stage A CLL patients compared with 12 healthy donors, we found a significant increase in recruitment of DNA-damage factors to telomeres showing telomere dysfunction in the early stage of the disease. Remarkably, the presence of dysfunctional telomeres did not correlate with telomere shortening or chromatin marks deregulation but with a down-regulation of 2 shelterin genes: ACD (coding for TPP1; P = .0464) and TINF2 (coding for TIN2; P = .0177). We propose that telomeric deprotection in the early step of CLL is not merely the consequence of telomere shortening but also of shelterin alteration.
authors.affiliation: Epigenetic and Telomeric Regulations, Lyon Sud Medicine Faculty, Lyon-1 University, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 5239, Pierre Bénite, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Augereau
authors.forename: Claire
authors.initials: C
authors.lastname: T'kint de Roodenbeke
authors.forename: Thomas
authors.initials: T
authors.lastname: Simonet
authors.forename: Serge
authors.initials: S
authors.lastname: Bauwens
authors.forename: Béatrice
authors.initials: B
authors.lastname: Horard
authors.forename: Mary
authors.initials: M
authors.lastname: Callanan
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.forename: Laurent
authors.initials: L
authors.lastname: Jallades
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.forename: Delphine
authors.initials: D
authors.lastname: Poncet
mesh_terms: D001483:Base Sequence; D015331:Cohort Studies; D004249:DNA Damage / Q000502:physiology*; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008954:Models, Biological; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D000089804:Shelterin Complex; D016615:Telomere / Q000235:genetics / Q000473:pathology*; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C495876:ACD protein, human; D012333:RNA, Messenger; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins