Accelerated telomere shortening and telomerase activation in Fanconi's anaemia
Accelerated telomere shortening and telomerase activation in Fanconi's anaemia
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DOI：
10.1046/j.1365-2141.1999.01445.x
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发表时间：
1999-06-01
影响因子：
6.5
通讯作者：
Gluckman, E
中科院分区：
文献类型：
--
作者：
Leteurtre, F;Li, X;Gluckman, E
范可尼贫血（Fanconi 'sanaemia，FA）是一种常染色体隐性遗传疾病，其特征是骨髓功能衰竭，常向急性白血病发展，属于染色体不稳定性疾病。由于端粒直接参与染色体稳定性和细胞增殖能力，我们研究了外周血单核细胞（PBMC）中的端粒代谢。54例FA患者的端粒长度显著短于51例对照组（P < 0.0001）。此外，平均端粒末端限制性片段长度（TRF）在9个杂合子患者样本没有不同于对照组。在14例患有严重再生障碍性贫血（SFA）的FA患者样本中，端粒长度显著短于22例年龄匹配的患有中度血液学异常（NSFA）的FA患者样本（P < 0.001）。然而，在另外16例单独分析的患者样本中，未发现TRF长度与骨髓克隆异常之间存在相关性。连续测量6例FA患者的TRF显示端粒缩短速率加快。因此，端粒缩短率与临床状态呈负相关。25例FA患者的端粒酶活性是15例年龄匹配的健康对照组的4.8倍。
Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure that often evolves towards acute leukaemia, FA also belongs to a group of chromosome instability diseases. Because telomeres are directly involved in chromosomal stability and in cell proliferation capacity, we examined telomere metabolism in peripheral blood mononuclear cells (PBMC). Telomere length was significantly shorter in 54 FA patient samples, compared to 51 controls (P < 0.0001). In addition, mean telomere terminal restriction fragment lengths (TRF) in nine heterozygous patient samples did not differ from those of controls. In 14 samples from FA patients with severe aplastic anaemia (SFA), telomere length was significantly shorter than in 22 samples of age-matched FA patients with moderate haematological abnormalities (NSFA) (P < 0.001). However, no correlation was found between TRF length and the presence of bone marrow clonal abnormalities in 16 additional, separately analysed, patient samples. Sequential measurement of TRF in six FA patients showed an accelerated rate of telomere shortening. Accordingly, telomere shortening rate was inversely correlated with clinical status. Telomerase, the enzyme that counteracts telomere shortening, was 4.8-fold more active in 25 FA patients than in 15 age-matched healthy controls, A model for the FA disease process is proposed.