Blood:竺晓凡/程涛教授团队取得重大突破,揭晓FLT3为PRC2突变T-ALL潜在治疗靶点!

2018-10-15 虚怀若谷 肿瘤资讯

近日,Blood杂志发表了一项来自中国的研究,中国医学科学院血液病医院的竺晓凡/程涛教授团队成功揭晓了儿童T细胞急淋(T-ALL)的治疗靶点。该研究证实了FMS样酪氨酸激酶3(FLT3)是组蛋白甲基化酶复合物2(PRC2)突变的儿童T-ALL患者的潜在治疗靶点,这具有重要的临床价值。

近日,Blood杂志发表了一项来自中国的研究,中国医学科学院血液病医院的竺晓凡/程涛教授团队成功揭晓了儿童T细胞急淋(T-ALL)的治疗靶点。该研究证实了FMS样酪氨酸激酶3(FLT3)是组蛋白甲基化酶复合物2(PRC2)突变的儿童T-ALL患者的潜在治疗靶点,这具有重要的临床价值。

研究背景

急性淋巴细胞白血病(ALL)是儿童最常见的恶性血液肿瘤,通常疗效及预后佳。但T细胞急淋(T-ALL)约占所有儿童ALL的15%左右,其危险度高、进展快及预后差,故而T-ALL的发病机制及治疗靶点成为重点研究方向之一。 组蛋白甲基化酶复合物2(PRC2)血细胞生成的关键调控因子之一,其核心组分包括SUZ12、EED以及EZH2,在接近25%的T-ALL患者中存在PRC2组分的基因突变。

研究内容

该研究共纳入60例原发性T-ALL患儿,并通过靶向基因测序发现,在12例T-ALL患儿中检测到PRC2组分的基因突变(共14个),分别为EZH2突变 (8/60)、SUZ12突变 (4/60)以及EED 突变(2/60)。通过回顾分析发现,伴有PRC2突变T-ALL患儿的骨髓原始细胞比例更高,为88.5% vs 81.72%, P = 0.026。

随后,通过RNA测序发现,在12例伴有PRC2突变的患儿中,FLT3的表达量明显上调,显著高于PRC2未突变的T-ALL患儿。此外,通过qRT-PCR方法进一步证实了FLT3的上调与PRC2突变存在特异性关联(详见图1),并且

EZH2突变(PRC2组分之一)的T-ALL患儿FLT3上调最为明显。



图1:PRC2突变的T-ALL患儿中,FLT3表达水平显著高于正常T细胞及未突变的T-ALL 

为进一步探索FLT3表达水平与PRC2突变之间的调控关系及机制,该研究通过CRISPR/Cas9技术对T-ALL细胞系Jukat的EZH2基因(PRC2组分之一)进行敲除。然后,通过Western-Blot的方法发现:在EZH2基因敲除的Jukat细胞中,FLT3表达及磷酸化水平显著上调(详见图2)。此外,FLT3信号通路明显激活,下游的STAT5、AKT以及 ERK表达水平增高(详见图3)。



图2:敲除EZH2基因的PRC2突变Jukat细胞(JE010/014/031)中磷酸化FLT3水平明显上调



图3:在敲除EZH2基因的PRC2突变Jukat细胞(JE010/014/031)中,FLT3信号通路明显激活,磷酸化的STAT5、AKT以及 ERK表达水平增高。 

在调控机制方面,该研究通过Chip-qPCR的方法证实了EZH2基因的敲除可导致H3K27me3表达下调及RNA聚合酶II(POLII)升高并在FLT3基因启动子区域结合,进而调控转录活性、调节FLT3的表达(详见图4)。



图4:可见H3K27me3表达下调及RNA聚合酶II(POLII)升高

此外值得注意的是,在EZH2基因敲除的T-ALL细胞中,即便已出现磷酸化的STAT5、AKT以及 ERK表达水平增高,但在应用FLT3抑制剂(索拉非尼、奎扎替尼)之后,STAT5、AKT以及 ERK表达水平可下调。并且,与PRC2未突变的T-ALL细胞相比较,FLT3小分子抑制剂索拉非尼(Sorafenib)和奎扎替尼(Quizartinib)对伴有PRC2突变的T-ALL原代细胞疗效更为敏感,这表明FLT3抑制剂是潜在治疗PRC2突变T-ALL患者的靶向药物。

结论

该研究通过多种实验方法(靶向测序、基因敲除+Western-Blot、Chip-qPCR及药物试验)、在多层面上阐述了T-ALL患儿中PRC2突变与FLT3信号通路的关系。明确的证实了FLT3是PRC2突变T-ALL患儿的潜在治疗靶点,有利于指导儿童T-ALL患者的精准治疗,改善儿童T-ALL的疗效及预后。 

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    2019-01-16 zhishijing
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    2018-10-17 膀胱癌
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    2018-10-17 紫砂壶
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    2018-10-17 fengyi816
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    2018-10-16 kafei

    学习了谢谢

    0