Accelerated telomere shortening precedes development of therapy-related myelodysplasia or acute myelogenous leukemia after autologous transplantation for lymphoma

J Clin Oncol. 2009 Feb 10;27(5):791-8. doi: 10.1200/JCO.2008.17.1033. Epub 2009 Jan 5.

Abstract

Purpose: 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.

Patients and 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Blotting, Southern
  • Cohort Studies
  • Female
  • Flow Cytometry
  • Hematopoietic Stem Cell Transplantation / adverse effects*
  • Hodgkin Disease / therapy
  • Humans
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / genetics*
  • Longitudinal Studies
  • Lymphoma / therapy*
  • Lymphoma, Non-Hodgkin / therapy
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / etiology*
  • Myelodysplastic Syndromes / genetics*
  • Prospective Studies
  • Telomere / physiology*
  • Transplantation, Autologous