title: Rapamycin safeguards lymphocytes from DNA damage accumulation in vivo.
abstract: Several studies reported the benefits of switching from anticalcineurins to mTOR inhibitors to avoid cancer occurrence after organ transplantation. The purpose of our study was to determine in vivo biological markers to explain these benefits. Cellular changes related to cellular senescence and DNA damage were analyzed in peripheral blood lymphocytes. Thirty-five kidney transplanted patients receiving anticalcineurins were investigated: 17 patients were proposed to switch to rapamycin and 18 patients with similar age and transplantation duration, continued anticalcineurins. Rapamycin effects were studied one year after the switch. Thirteen healthy volunteers and 18 hemodialyzed patients were evaluated as control. Compared with the healthy group, hemodialyzed and transplanted patients exhibited a significant decrease in telomere length, an increase in p16(INK4A) mRNA expression and in lymphocytes with 53BP1 foci. A destabilization of the shelterin complexes was suggested by a significant TIN2 mRNA decrease in transplanted patients compared with controls and a significant increase in TRF1, TRF2 and POT1 expression in switch-proposed patients compared with the non-switched subgroup. Rapamycin treatment resulted in a significant decrease in DNA damage and a slight TIN2 increase. In vitro experiments strengthened in vivo results showing that rapamycin but not FK506 induced a significant DNA damage decrease and TIN2 expression increase compared with controls. The roles of rapamycin in the decrease in DNA damage in vivo and the rescue of shelterin gene expression are demonstrated for the first time. These data provide new insights into understanding of how rapamycin may overcome genomic injuries.
authors.affiliation: Clinical and Experimental Models of Lymphomagenesis, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052 - CNRS UMR5286 Centre Léon Bérard, Faculté de Médecine Lyon Sud, Oullins, France.
authors.forename: Amel
authors.initials: A
authors.lastname: Chebel
authors.affiliation: Clinical and Experimental Models of Lymphomagenesis, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052 - CNRS UMR5286 Centre Léon Bérard, Faculté de Médecine Lyon Sud, Oullins, France.
authors.forename: Régine
authors.initials: R
authors.lastname: Catallo
authors.affiliation: Clinical and Experimental Models of Lymphomagenesis, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052 - CNRS UMR5286 Centre Léon Bérard, Faculté de Médecine Lyon Sud, Oullins, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Mabon
authors.affiliation: Service d'Hématologie, Centre Hospitalier Lyon Sud (CHLS), HCL, Pierre-Bénite, France; INSERM U1111, Centre International de Recherche en Infectiologie, Université de Lyon, Lyon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bachy
authors.affiliation: Clinical and Experimental Models of Lymphomagenesis, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052 - CNRS UMR5286 Centre Léon Bérard, Faculté de Médecine Lyon Sud, Oullins, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wenner
authors.affiliation: Clinical and Experimental Models of Lymphomagenesis, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052 - CNRS UMR5286 Centre Léon Bérard, Faculté de Médecine Lyon Sud, Oullins, France; Service d'Hématologie, Centre Hospitalier Lyon Sud (CHLS), HCL, Pierre-Bénite, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: Service de Transplantation, Néphrologie et Immunologie Clinique de l'Hôpital Edouard Herriot, HCL, Université Lyon 1, Lyon, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Pouteil-Noble
authors.affiliation: Clinical and Experimental Models of Lymphomagenesis, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052 - CNRS UMR5286 Centre Léon Bérard, Faculté de Médecine Lyon Sud, Oullins, France; Service d'Hématologie, Centre Hospitalier Lyon Sud (CHLS), HCL, Pierre-Bénite, France. Electronic address: ffrenchma@gmail.com.
authors.forename: Martine
authors.initials: M
authors.lastname: Ffrench
mesh_terms: D000368:Aged; D065095:Calcineurin Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D004249:DNA Damage / Q000187:drug effects*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D007674:Kidney Diseases / Q000097:blood / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods*; D008214:Lymphocytes / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000627:therapeutic use*; D016615:Telomere / Q000187:drug effects
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D020123:Sirolimus
keywords: Calcineurin inhibitors; DNA damage; Lymphocytes; Rapamycin; Telomere length