Accelerated telomere shortening precedes development of therapy-related myelodysplasia or acute myelogenous leukemia after autologous transplantation for lymphoma.
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.
Chakraborty
Sujata
S
Department of Stem Cell and Leukemia Research, Division of Population Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA.
Sun
Can-Lan
CL
Francisco
Liton
L
Sabado
Melanie
M
Li
Liang
L
Chang
Karen L
KL
Forman
Stephen
S
Bhatia
Smita
S
Bhatia
Ravi
R
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