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ATR-Chk1轴可保护BCR/ABL白血病细胞免受DNA双链断裂的致死效应。

ATR-Chk1 axis protects BCR/ABL leukemia cells from the lethal effect of DNA double-strand breaks.

作者信息

Nieborowska-Skorska Margaret, Stoklosa Tomasz, Datta Mandrita, Czechowska Agnieszka, Rink Lori, Slupianek Artur, Koptyra Mateusz, Seferynska Ilona, Krszyna Konrad, Blasiak Janusz, Skorski Tomasz

机构信息

Department of Microbiology and Immunology, Temple University, Philadelphia, Pennsylvania 19140, USA.

出版信息

Cell Cycle. 2006 May;5(9):994-1000. doi: 10.4161/cc.5.9.2722. Epub 2006 May 1.

Abstract

BCR/ABL-positive leukemia cells accumulated more replication-dependent DNA double-strand breaks (DSBs) than normal counterparts after treatment with cisplatin and mitomycin C (MMC, as assessed by pulse field gel electrophoresis (PFGE) and neutral comet assay. In addition, leukemia cells could repair these lesions more efficiently than normal cells and eventually survive genotoxic treatment. Elevated levels of drug-induced DSBs in leukemia cells were associated with higher activity of ATR kinase, and enhanced phosphorylation of histone H2AX on serine 139 (gamma-H2AX). gamma-H2AX eventually started to disappear in BCR/ABL cells, while continued to increase in parental cells. In addition, the expression and ATR-mediated phosphorylation of Chk1 kinase on serine 345 were often more abundant in BCR/ABL-positive leukemia cells than normal counterparts after genotoxic treatment. Inhibition of ATR kinase by caffeine but not Chk1 kinase by indolocarbazole inhibitor, SB218078 sensitized BCR/ABL leukemia cells to MMC in a short-term survival assay. Nevertheless, both caffeine and SB218078 enhanced the genotoxic effect of MMC in a long-term clonogenic assay. This effect was associated with the abrogation of transient accumulation of leukemia cells in S and G2/M cell cycle phases after drug treatment. In conclusion, ATR-Chk1 axis was strongly activated in BCR/ABL-positive cells and contributed to the resistance to DNA cross-linking agents causing numerous replication-dependent DSBs.

摘要

与正常细胞相比,经顺铂和丝裂霉素C(MMC)处理后,BCR/ABL阳性白血病细胞积累了更多依赖复制的DNA双链断裂(DSB)(通过脉冲场凝胶电泳(PFGE)和中性彗星试验评估)。此外,白血病细胞比正常细胞能更有效地修复这些损伤,并最终在基因毒性治疗中存活下来。白血病细胞中药物诱导的DSB水平升高与ATR激酶活性增加以及组蛋白H2AX丝氨酸139位点(γ-H2AX)的磷酸化增强有关。γ-H2AX最终在BCR/ABL细胞中开始消失,而在亲代细胞中持续增加。此外,在基因毒性治疗后,BCR/ABL阳性白血病细胞中Chk1激酶丝氨酸345位点的表达和ATR介导的磷酸化通常比正常细胞更丰富。在短期存活试验中,咖啡因抑制ATR激酶而非吲哚咔唑抑制剂SB218078抑制Chk1激酶可使BCR/ABL白血病细胞对MMC敏感。然而,在长期克隆形成试验中,咖啡因和SB218078均增强了MMC的基因毒性作用。这种作用与药物处理后白血病细胞在S期和G2/M期短暂积累的消除有关。总之,ATR-Chk1轴在BCR/ABL阳性细胞中被强烈激活,并导致对引起大量依赖复制的DSB的DNA交联剂产生抗性。

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