title: Long-term lymphoma survivors following high-dose chemotherapy and autograft: evidence of permanent telomere shortening in myeloid cells, associated with marked reduction of bone marrow hematopoietic stem cell reservoir.
abstract: OBJECTIVE
  To investigate telomere length (TL) and hematopoietic progenitors in long-term survivors after high-dose chemotherapy and peripheral blood stem cell (PBSC) autograft.
  
  
  METHODS
  Peripheral blood (PB) and bone marrow (BM) samples were obtained from 31 subjects in continuous complete remission from a high-risk lymphoma, at a median of 5.8 years (range: 1-11 years) since autograft. Most of them were grafted with large PBSC quantities (median CD34(+ve) cells/kg: 7 x 10(6)). TL was determined by Southern blot analysis, BM progenitors by in vitro long-term culture-initiating cells (LTC-IC) and colony assays.
  
  
  RESULTS
  TL of PB granulocytes was significantly shortened in autografted subjects compared with age-matched healthy subjects; a similar finding was observed in BM. The median TL reduction in granulocytes from autografted subjects compared with age-matched controls (Delta(TelShortening)) was then assessed according to time interval since autograft. Three subject subgroups were identified-at 1 to <3 years, 3 to <6 years, and 6 to 11 years since autograft-and their telomere loss was the same, with Delta(TelShortening) of 1132, 1379, and 1214 bp in the three subgroups, respectively. The longitudinal assessment of TL in five representative patients followed for up to 40 months since autograft confirmed that telomere shortening occurring during exposure to chemotherapy as well as postautograft is persistent at long term. BM LTC-IC and multipotent and committed progenitors were assessed in subjects at >3 years after autograft and found to be markedly reduced compared with normal controls.
  
  
  CONCLUSIONS
  High-dose chemotherapy and PBSC autograft may result in myelopoietic cell abnormalities that appear to be irreversible.
authors: Divisione di Ematologia, Dipartimento di Medicina ed Oncologia Sperimentale-Universitá di Torino, Italy.
authors: Alberto
authors: A
authors: Rocci
authors: Irene
authors: I
authors: Ricca
authors: Chiara
authors: C
authors: Dellacasa
authors: Paolo
authors: P
authors: Longoni
authors: Mara
authors: M
authors: Compagno
authors: Roberto
authors: R
authors: Francese
authors: Chiara
authors: C
authors: Lobetti Bodoni
authors: Paola
authors: P
authors: Manzini
authors: Daniele
authors: D
authors: Caracciolo
authors: Mario
authors: M
authors: Boccadoro
authors: Dario
authors: D
authors: Ferrero
authors: Marco
authors: M
authors: Ladetto
authors: Carmelo
authors: C
authors: Carlo-Stella
authors: Corrado
authors: C
authors: Tarella
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000601:surgery / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D017741:Survivors; D016615:Telomere
chemical_list: D000970:Antineoplastic Agents