PML-RARα异常调控CST7-CTSS轴影响急性早幼粒细胞白血病细胞分化  

Abnormal regulation of CST7-CTSS axis by PML-RARα affects differentiation of acute promyelocytic leukemia cells

作　　者：李子平 卫凤桂[2] 梁文怡 符祥猛 徐浩育 张辉 LI Ziping;WEI Fenggui;LIANG Wenyi;FU Xiangmeng;XU Haoyu;ZHANG Hui(Department of Hematology and Oncology,Guangzhou Women and Children′s Medical Center,Guangzhou 510623,China;Department of Pediatrics,The First Affiliated Hospital of Guangzhou Medical University,Guangzhou 510120,China;School of Pediatrics,Guangzhou Medical University,Guangzhou 510121,China)

机构地区：[1]广州市妇女儿童医疗中心血液肿瘤科,广州510623 [2]广州医科大学附属第一医院儿科,广州510120 [3]广州医科大学儿科学院,广州510121

出　　处：《中国小儿血液与肿瘤杂志》2020年第6期323-328,共6页Journal of China Pediatric Blood and Cancer

基　　金：广州医科大学大学生开放项目(B185004122);儿研所项目(IP-2018-001);广东省自然科学基金项目(2015A030313460)。

摘　　要：目的研究CST7-CTSS轴在急性早幼粒细胞白血病(APL)发病中的作用。方法收集急性髓系白血病表达谱数据集,进行相关性分析明确融合基因PML-RARα与CST7的表达关系,并对其靶蛋白酶进行相关性分析。结果通过RT-qPCR评价PML-RARα对CST7-CTSS轴的影响。通过敲低CST7表达,检测其对APL细胞分化的影响。通过相关性分析发现CST7仅在携带PML-RARα的APL患者中显著增高。随着全反式维甲酸(ATRA)诱导APL分化,CST7基因表达逐渐降低;利用Zn剂处理PR9细胞诱导PML-RARα表达后,CST7 mRNA表达水平明显增高。生物信息分析显示CTSS是CST7的潜在上游蛋白,在APL中显著低表达;CTSS表达水平随着APL细胞诱导分化逐渐上调。敲低CST7基因,能部分易化ATRA诱导APL细胞分化。结论PML-RARα可能直接转录激活CST7,进而影响其靶蛋白酶的功能。CTSS是CST7的潜在靶蛋白酶之一,ATRA可能逆转CST7-CTSS的病理性异常以改善APL治疗。Objective To explore the role of CST7-CTSS axis in the pathogenesis of acute promyelocytic leukemia(APL).Methods Expression correlation between the fusion gene PML-RARαand CST7 and its target proteases was analyzed using acute myeloid leukemia expression profile data set.RT-qPCR was performed to evaluate the effect of PML-RARαon the CST7-CTSS axis.CST7 knock-down experiment was performed to define its effect on APL differentiation.Results Gene expression prolife analysis showed that CST7 was selectively higher expressed in APL patients with PML-RARαfusion gene.CST7 expression was gradually decreased during all-trans retinoic acid(ATRA)-induced APL differentiation.Using PR9(inducible PML-RARαcells)cell line as study model,increased CST7 expression was identified upon Zn2+-induced PML-RARαexpression.Bioinformatics analysis indicated that CTSS potentially interacted with CST7.The expression of CTSS was gradually increased during APL cell differentiation.Knocking down CST7 gene expression partially facilitated ATRA-induced APL cell differentiation.Conclusions PML-RARαpotentially activates CST7 transcription,thereby affecting the function of its target protease.CTSS is a potential target protease of CST7.ATRA reverses the pathological abnormality of CST7-CTSS,might in turn contribute to APL therapy.

关 键 词：CST7 CTSS 急性早幼粒细胞白血病 诱导分化 

分 类 号：R73[医药卫生—肿瘤]