Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia.

Abstract:

:In cell and animal models, telomere erosion promotes chromosomal instability via breakage-fusion-bridge cycles, contributing to the early stages of tumorigenesis. However, evidence involving short telomeres in cancer development in humans is scarce, epidemiological and indirect. Here we directly implicate telomere shortening as a critical molecular event for malignant evolution in aplastic anemia (AA). Patients' telomere lengths at diagnosis of AA, while comparable to age-matched controls, inversely correlated with the probability of developing a cytogenetically abnormal clone. A significantly increased number of telomere signal-free chromosomal ends and chromosomal numerical and structural abnormalities were observed in bone marrow cells of patients with shorter telomeres in comparison with patients with longer telomeres and healthy subjects. The proportion of monosomy-7 cells in the bone marrow at diagnosis of AA inversely correlated with telomere length, years before the emergence of an autonomous and clinically detectable abnormal clone. Marrow cells of clinically healthy individuals carrying loss-of-function telomerase mutations and with extremely short telomeres also showed chromosomal instability in vitro. These results provide the first clinical direct evidence in humans that short telomeres in hematopoietic cells are dysfunctional, mediate chromosomal instability and predispose to malignant transformation in a human disease.

journal_name

Leukemia

journal_title

Leukemia

authors

Calado RT,Cooper JN,Padilla-Nash HM,Sloand EM,Wu CO,Scheinberg P,Ried T,Young NS

doi

10.1038/leu.2011.272

subject

Has Abstract

pub_date

2012-04-01 00:00:00

pages

700-7

issue

4

eissn

0887-6924

issn

1476-5551

pii

leu2011272

journal_volume

26

pub_type

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