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

Abstract

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. 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. 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. 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.