title: Accelerated telomere shortening precedes development of therapy-related myelodysplasia or acute myelogenous leukemia after autologous transplantation for lymphoma.
abstract: OBJECTIVE
  Therapy-related myelodysplasia or acute myelogenous leukemia (t-MDS/AML) is a lethal complication of autologous hematopoietic stem-cell transplantation (aHCT) for Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). Here, we investigated the hypothesis that accelerated telomere shortening after aHCT could contribute to the development of t-MDS/AML.
  
  
  METHODS
  A prospective longitudinal cohort was constructed to investigate the sequence of cellular and molecular abnormalities leading to development of t-MDS/AML after aHCT for HL/NHL. This cohort formed the sampling frame for a nested case-control study to compare changes in telomere length in serial blood samples from patients who developed t-MDS/AML with matched controls who did not develop t-MDS/AML.
  
  
  RESULTS
  An initial increase in telomere length at day 100 after aHCT was followed by an accelerated telomere shortening in t-MDS/AML patients when compared with controls. These telomere alterations preceded the onset of t-MDS and were independent of other known risk factors associated with development of t-MDS/AML on multivariate analysis. Additionally, we observed reduced generation of committed progenitors in patients who developed t-MDS/AML, indicating that these telomere alterations were associated with reduced regenerative capacity of hematopoietic stem cells.
  
  
  CONCLUSIONS
  The development of t-MDS/AML after aHCT is associated with and preceded by markedly altered telomere dynamics in hematopoietic cells. Accelerated telomere loss in patients developing t-MDS/AML may reflect increased clonal proliferation and/or altered telomere regulation in premalignant cells. Genetic instability associated with shortened telomeres may contribute to leukemic transformation in t-MDS/AML.
authors.affiliation: Department of Stem Cell and Leukemia Research, Division of Population Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Can-Lan
authors.initials: CL
authors.lastname: Sun
authors.forename: Liton
authors.initials: L
authors.lastname: Francisco
authors.forename: Melanie
authors.initials: M
authors.lastname: Sabado
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Karen L
authors.initials: KL
authors.lastname: Chang
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Smita
authors.initials: S
authors.lastname: Bhatia
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D015139:Blotting, Southern; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006689:Hodgkin Disease / Q000628:therapy; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics*; D008137:Longitudinal Studies; D008223:Lymphoma / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000209:etiology* / Q000235:genetics*; D011446:Prospective Studies; D016615:Telomere / Q000502:physiology*; D014182:Transplantation, Autologous