Resistance to Imatinib Mesylate-induced apoptosis in acute lymphoblastic leukemia is associated with PTEN down-regulation due to promoter hypermethylation
Resistance to Imatinib Mesylate-induced apoptosis in acute lymphoblastic leukemia is associated with PTEN down-regulation due to promoter hypermethylation
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DOI：
10.1016/j.leukres.2007.09.005
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发表时间：
2008-05-01
影响因子：
2.7
通讯作者：
Prosper, Felipe
中科院分区：
文献类型：
--
作者：
Montiel-Duarte, Cristina;Cordeu, Lucia;Prosper, Felipe
本研究的目的是确定Ph+ ALL患者伊马替尼耐药的潜在机制。Ph+ ALL细胞对伊马替尼诱导的凋亡的抵抗与Akt磷酸化缺乏抑制有关。在伊马替尼中加入PI 3 K抑制剂LY 294002可显著增加Ph+ ALL细胞的凋亡。有趣的是，在Ph+ ALL细胞中，PTEN的表达降低，这是由于PTEN启动子高甲基化。用5-氮杂-2 '-脱氧胞苷处理Ph+ ALL细胞与PTEN表达增加和细胞凋亡增加相关。这些结果表明，伊马替尼耐药的ALL患者可能至少部分依赖于PTEN的下调，由于异常的启动子高甲基化和支持的潜在作用，去甲基化剂治疗Ph+ ALL患者。(C)2007爱思唯尔有限公司保留所有权利。
The aim of our study was to determine the potential mechanism(s) implicated in Imatinib resistance in patients with Ph+ ALL. Resistance of Ph+ ALL cells to Imatinib-induced apoptosis was associated with lack of inhibition of Akt phosphorylation. Addition of the PI3K inhibitor LY294002 to Imatinib significantly increased apoptosis of Ph+ ALL cells. Interestingly, expression of PTEN was reduced in Ph+ ALL cells which was due to PTEN promoter hypermethylation. Treatment of Ph+ ALL cells with 5-Aza-2'-deoxycytidine was associated with an increased expression of PTEN and an increase in cell apoptosis. These results suggest that Imatinib resistance in patients with ALL may be dependent at least in part to PTEN down-regulation due to the abnormal promoter hypermethylation and support the potential role of de-methylating agents for the treatment of patients with Ph+ ALL. (C) 2007 Elsevier Ltd. All rights reserved.