PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia
PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia
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PTEN 是消除慢性粒细胞白血病中由 GSK126 靶向 EZH2 介导的白血病干细胞的基础
DOI：
10.1158/1078-0432.ccr-17-1533
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发表时间：
2018-01-01
影响因子：
11.5
通讯作者：
Pan, Jingxuan
中科院分区：
文献类型：
--
作者：
Zhou, Jingfeng;Nie, Danian;Pan, Jingxuan
目的：白血病干细胞（LSC）是慢性粒细胞白血病（CML）患者对酪氨酸激酶抑制剂耐药和疾病复发的重要来源。瞄准LSC可能是克服这一棘手问题的一个有吸引力的策略。鉴于EZH 2在原代CML CD 34棘细胞中过表达，本研究的目的是评估靶向EZH 2对CML LSCs的影响并阐明其潜在的机制。实验设计：采用人原代CML CD 34棘细胞和逆转录病毒BCR-ABL驱动的CML小鼠模型，评估GSK 126或EZH 2特异性shRNA在体外和体内抑制EZH 2的效果。结果：GSK 126对EZH 2和H3 K27 me 3的抑制作用不仅能诱导CML细胞凋亡，抑制细胞生长，而且能降低CML细胞中的LSC，而对正常骨髓CD 34棘细胞中的LSC无明显影响。通过GSK 126或特异性shRNA抑制EZH 2延长了CML小鼠的存活时间，并减少了小鼠中LSC的数量。EZH 2基因敲低导致PTEN基因表达升高，并导致EZH 2和H3 K27 me 3在PTEN基因启动子上的募集受损。EZH 2基因敲低在CML小鼠中的效果至少部分地被逆转的PTEN knockdown.Conclusions：这些研究结果提高了对CML LSCs中干性的表观遗传调控的理解，并保证了GSK 126在难治性CML患者中的临床试验。临床癌症（C）2017 AACR。
Purpose: Leukemia stem cells (LSCs) are an important source of tyrosine kinase inhibitor resistance and disease relapse in patients with chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that EZH2 was overexpressed in primary CML CD34 thorn cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism.Experimental Design: Human primary CML CD34 thorn cells and retrovirally BCR-ABL-driven CML mouse models were employed to evaluate the effects of suppression of EZH2 by GSK126-or EZH2-specific shRNA in vitro and in vivo. Recruitment of EZH2 and H3K27me3 on the promoter of tumorsuppressor gene PTEN in CML cells wasmeasured by chromatin immunoprecipitation assay.Results: Our results showed that pharmacologic inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34 thorn cells while sparing those from normal bone marrow CD34 thorn cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. EZH2 knockdown resulted in elevation of PTEN and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of PTEN gene. The effect of EZH2 knockdown in the CML mice was at least partially reversed by PTEN knockdown.Conclusions: These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs and warrant clinical trial of GSK126 in refractory patients with CML. Clin Cancer (C) 2017 AACR.