Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis
Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis
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DOI：
10.1182/blood-2010-02-272104
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发表时间：
2010-09-16
期刊：
影响因子：
20.3
通讯作者：
Baird, Duncan M.
中科院分区：
文献类型：
--
作者：
Lin, Thet Thet;Letsolo, Boitelo T.;Baird, Duncan M.
我们对不同阶段的慢性淋巴细胞白血病(CLL)患者进行了单分子端粒长度和端粒融合分析。我们的工作确定了人类原始组织中记录到的最短的端粒，强化了CLL存在显著细胞分裂的概念。此外，我们提供了直接证据表明，关键的端粒缩短、功能障碍和融合有助于疾病的进展。短端粒和融合事件的频率随着疾病的进展而增加，但重要的是，在早期患者样本的子集中也发现了这些事件，表明这些事件可以先于疾病进展。从端粒最短的人群中分离出的融合事件的序列分析显示，断点处的重复数、端粒下缺失和微同源性有限。对显示端粒功能障碍证据的人进行的阵列比较基因组杂交分析显示，大规模的基因组重排集中在端粒区域；这在端粒较长的样本中没有观察到。在CLL B细胞中观察到的端粒动力学与在P53途径被取消后经历培养危机的细胞中观察到的端粒动力学没有区别。综上所述，我们的数据支持端粒侵蚀和随后的端粒融合在CLL的进展中至关重要的概念，并且这一范例可能扩展到其他恶性肿瘤。(血。2010年；116(11)：1899-1907)
We performed single-molecule telomere length and telomere fusion analysis in patients at different stages of chronic lymphocytic leukemia (CLL). Our work identified the shortest telomeres ever recorded in primary human tissue, reinforcing the concept that there is significant cell division in CLL. Furthermore, we provide direct evidence that critical telomere shortening, dysfunction, and fusion contribute to disease progression. The frequency of short telomeres and fusion events increased with advanced disease, but importantly these were also found in a subset of early-stage patient samples, indicating that these events can precede disease progression. Sequence analysis of fusion events isolated from persons with the shortest telomeres revealed limited numbers of repeats at the breakpoint, subtelomeric deletion, and microhomology. Array-comparative genome hybridization analysis of persons displaying evidence of telomere dysfunction revealed large-scale genomic rearrangements that were concentrated in the telomeric regions; this was not observed in samples with longer telomeres. The telomere dynamics observed in CLL B cells were indistinguishable from that observed in cells undergoing crisis in culture after abrogation of the p53 pathway. Taken together, our data support the concept that telomere erosion and subsequent telomere fusion are critical in the progression of CLL and that this paradigm may extend to other malignancies. (Blood. 2010; 116(11): 1899-1907)