Originally published as JCO Early Release 10.1200/JCO.2008.17.1033 on January 5 2009

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Accelerated Telomere Shortening Precedes Development of Therapy-Related Myelodysplasia or Acute Myelogenous Leukemia After Autologous Transplantation for Lymphoma

From the Department of Stem Cell and Leukemia Research, Division of Population Sciences, Division of Pathology, Division of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA.

Corresponding author: Ravi Bhatia, MD, Department of Hematopoietic Stem Cell and Leukemia Research, Division of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010; e-mail: rbhatia{at}coh.org.

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.

Supported by National Institutes of Health Grant No. P50CA107399 from the National Cancer Institute and General Clinical Research Center Grant No. 5M01 RR00043.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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