Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Leukemia. 2012 Apr;26(4):700-7. doi: 10.1038/leu.2011.272. Epub 2011 Oct 18.
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.
在细胞和动物模型中，端粒磨损通过断裂-融合-桥循环促进染色体不稳定性，导致肿瘤发生的早期阶段。然而，涉及人类癌症发展中短端粒的证据很少，而且是流行病学和间接的。在这里，我们直接将端粒缩短作为再生障碍性贫血 (AA) 恶性演变的关键分子事件。AA 患者在诊断时的端粒长度与年龄匹配的对照组相当，但与发生细胞遗传学异常克隆的概率成反比。与端粒较长的患者和健康受试者相比，端粒较短的患者骨髓细胞中观察到端粒信号缺失的染色体末端数量增加，以及染色体数目和结构异常增加。在 AA 诊断时，骨髓中单倍体-7 细胞的比例与端粒长度呈反比，这在自主且临床上可检测到的异常克隆出现之前的数年就已出现。携带功能丧失端粒酶突变且端粒极短的临床健康个体的骨髓细胞在体外也表现出染色体不稳定性。这些结果提供了人类中第一个临床直接证据，证明造血细胞中的短端粒功能失调，介导染色体不稳定性并导致人类疾病中的恶性转化。
