Inactivation of PTEN increases ABCG2 expression and the side population through the PI3K/Akt pathway in adult acute leukemia
Inactivation of PTEN increases ABCG2 expression and the side population through the PI3K/Akt pathway in adult acute leukemia
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PTEN 失活通过 PI3K/Akt 通路增加成人急性白血病中 ABCG2 的表达和侧群
DOI：
10.1016/j.canlet.2013.04.006
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发表时间：
2013-08-09
期刊：
影响因子：
9.7
通讯作者：
Zeng, Hui
中科院分区：
文献类型：
--
作者：
Huang, Fang-Fang;Wu, Deng-Shu;Zeng, Hui
急性白血病(AL)的发生和复发可能提示白血病干细胞的存在。侧群(SP)细胞表现出干细胞样特性，表达ABCG2(乳腺癌耐药蛋白[BCRP])。研究发现，ABCG2在Jurkat和HL60细胞中过表达导致P物质含量增加，磷酸化PI3K和磷酸化Akt水平上调，并增强耐药性，这些都可以被PI3K抑制剂LY294002或mTOR抑制剂雷帕霉素所减弱。对222例初诊、缓解期和难治复发(R/R)成人AL患者的ABCG2表达和SP细胞计数进行分析，并以10例健康献血者作为正常对照。在急性髓系白血病(AML)和急性淋巴细胞白血病(ALL)患者中，仅观察到一小部分ABCG2+细胞(0.05-12.3%)和SP细胞(0.02-1.60%)。在正常对照人群中，在AML和ALL中，与确诊或复发时的SP细胞比例相比，SP细胞比例在统计学上更高。此外，我们还证明，ABCG2的表达和SP细胞比例可以通过取消PI3K/Alct通路的抑制而通过磷酸酶和张力蛋白同源蛋白(PTEN)的失活来上调。总之，这项研究表明PTEN/PI3K/Akt通路上调ABCG2的表达和SP细胞群，是一个潜在的AL特异性治疗靶点，值得进一步研究。(C)2013爱思唯尔爱尔兰有限公司。保留所有权利。
Both the occurrence and recurrence of acute leukemia (AL) might suggest the presence of leukemia stem cells. Side population (SP) cells, exhibiting stem cell-like properties, express ABCG2 (breast cancer resistance protein [BCRP]). This study revealed that over-expression of ABCG2 in Jurkat and HL60 cells led to an increased SP fraction, up-regulated levels of phosphorylated-PI3K and phosphorylated-Akt, and enhanced drug resistance, all of which could be attenuated by treatment with either the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin. ABCG2 expression and SP cell counts were further characterized in 222 adult AL patients at three disease stages: upon diagnosis, at remission and at refractory/relapse (R/R), while 10 healthy donors served as the normal controls. Only a small fraction of the ABCG2 + population (0.05-12.3%) and SP cells (0.02-1.60%) were observed in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. In the normal control population, the SP cell fraction represented a statistically higher percentage of total cells compared to the fraction of SP cells upon diagnosis or relapse in both AML and ALL In addition, we demonstrated that ABCG2 expression and SP cell ratios can be upregulated by the inactivation of phosphatase and tensin homolog (PTEN) protein, achieved in this study by removing inhibition of the PI3K/Alct pathway. Collectively, this study suggests that the PTEN/PI3K/Akt pathway up-regulates ABCG2 expression and the SP cell population and is a potential AL-specific treatment target worth investigating further. (C) 2013 Elsevier Ireland Ltd. All rights reserved.