Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nophomologous end-joining DNA repair pathway
Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nophomologous end-joining DNA repair pathway
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DOI：
10.1182/blood-2004-07-2888
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发表时间：
2005-06-15
期刊：
影响因子：
20.3
通讯作者：
Delic, J
中科院分区：
文献类型：
--
作者：
Deriano, L;Guipaud, O;Delic, J
非同源末端连接（NHEJ） DNA因子通过其DNA双链断裂（DSB）修复和端粒相关活性维持基因组稳定性。未修复或错误修复的dsb可导致细胞凋亡或染色体损伤。一些B-慢性淋巴细胞白血病（B- cll）患者的B细胞对辐射诱导的体外凋亡具有抵抗性。我们在这里表明，新的DNA依赖性蛋白激酶（DNA- pk）抑制剂NU7026 （2-(morpholin-4-yl)-benzo[h] chomen1 - 1）和磷脂酰肌醇3 （PI-3）激酶抑制剂wortmannin可以恢复DNA损伤诱导的耐药细胞凋亡的敏感性。这些耐药的恶性B细胞在暴露于依托泊苷或新ocarzinostatatin后也逃脱了dsb诱导的凋亡。我们发现，在辐照后15分钟，NHEJ水平（通过体外DSB末端连接试验测量）和DNA-PK催化亚基（DNA-PKcs）活性在耐辐射的B- cll细胞和eb病毒转化的B细胞中分别高出2倍和4倍。耐药B-CLL细胞亚群中Ku70/Ku80异源二聚体DNA末端结合活性也比敏感B-CLL细胞亚群高2- 3倍。我们的研究结果提供了第一个证据，证明过度激活NHEJ DNA修复途径会损害恶性B细胞中DNA损伤诱导的凋亡，这可能有助于它们对当前化疗的抵抗。(c) 2005年由美国血液学会出版
Nonhomologous end-joining (NHEJ) DNA factors maintain genomic stability through their DNA double-strand break (DSB) repair and telomere-associated activities. Unrepaired or misrepaired DSBs can lead to apoptotic death or chromosomal damage. The B cells of some B-chronic lymphocytic leukemia (B-CLL) patients are resistant to radiation-induced apoptosis in vitro. We show here that the novel DNA-dependent protein kinase (DNA-PK) inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), and the phosphatidylinositol 3 (PI-3) kinase inhibitor, wortmannin, restored sensitivity to DNA damage-induced apoptosis of otherwise resistant cells. These resistant malignant B cells also escaped DSB-induced apoptosis following exposure to etoposide or neocarzinostatin. We found that at 15 minutes after irradiation, the levels of NHEJ (as measured by an in vitro DSB end-ligation assay) and DNA-PK catalytic subunit (DNA-PKcs) activity were, respectively, 2-fold and 4-fold higher in radioresistant than in radio-sensitive B-CLL cells or Epstein-Barr virus (EBV)-transformed B cells. Ku70/Ku80 heterodimer DNA end-binding activity was also 2- to 3-fold higher in the resistant B-CLL cell subset compared with the sensitive B-CLL cell subset. Our results provide the first evidence that overactivating the NHEJ DNA repair pathway impairs DNA damage-induced apoptosis in malignant B cells and that this may contribute to their resistance to current chemotherapy. (c) 2005 by The American Society of Hematology