中国癌症杂志 ›› 2020, Vol. 30 ›› Issue (8): 577-585.doi: 10.19401/j.cnki.1007-3639.2020.08.003

• 论著 • 上一篇    下一篇

SOCS1的表观遗传学修饰与急性髓系白血病的关系

张晓慧 1 ,罗建民 2 ,索晓慧 1 ,孙国锋 1 ,刘洪峰 1 ,李 静 3 ,牛广旭 4   

  1. 1. 河北省邯郸市中心医院血液内科,河北 邯郸 056001 ;
    2. 河北医科大学第二医院血液内科,河北 石家庄 050000 ;
    3. 河北省邯郸市中心医院肿瘤内科,河北 邯郸 056001 ;
    4. 河北省邯郸市中心医院病理科,河北 邯郸 056001
  • 出版日期:2020-08-30 发布日期:2020-09-03
  • 通信作者: 张晓慧 E-mail: zhangxiaohuiqq@163.com
  • 基金资助:
    河北省卫生健康委员会科研基金(20190195)。

Relationship between epigenetic modification of SOCS1 and acute myeloid leukemia

ZHANG Xiaohui 1 , LUO Jianmin 2 , SUO Xiaohui 1 , SUN Guofeng 1 , LIU Hongfeng 1 , LI Jing 3 , NIU Guangxu 4   

  1. 1.Department of Hematology, Handan Central Hospital, Handan 056001, Hebei Province, China; 2. Department of Hematology, The Second Hospital of Hebei Medical University, Key Laboratory of Hematology, Shijiazhuang 050000, Hebei Province, China; 3. Department of Oncology, Handan Central Hospital, Handan 056001, Hebei Province, China; 4. Department of Pathology, Handan Central Hospital, Handan 056001, Hebei Province, China
  • Published:2020-08-30 Online:2020-09-03
  • Contact: ZHANG Xiaohui E-mail: zhangxiaohuiqq@163.com

摘要: 背景与目的:细胞因子信号转导抑制因子1 (suppressor of cytokine signaling 1,SOCS1)是公认的抑癌基因,研究SOCS1基因的表观遗传学修饰与急性髓系白血病发生、发展的关系。方法:采用反转录聚合酶链反应(reverse transcription polymerase chain reaction,RT-PCR)、甲基化特异性PCR(methylation-specific PCR,MS-PCR)、蛋白质印迹法(Western blot)、体外细胞培养、药物干预、细胞增殖检测、基因敲除等技术,分析2016年2月—2018年12月邯郸市中心医院血液内科和河北省医科大学第二医院血液内科收治的110例急性髓系白血病患者及白血病细胞系U937和THP-1中SOCS1基因的表达、甲基化状态和疾病发生、发展的关系。同时分析SOCS1表观遗传学改变相关基因DNA甲基转移酶1(DNA methyltransferase 1,DNMT1)和DNMT3a及组蛋白去乙酰化酶1(histone deacetylase 1,HDAC1)基因的变化。结果:在急性髓系白血病初治组和复发难治组中SOCS1基因甲基化率显著高于缓解组和正常对照组(48%和80% vs 0%和0%),其mRNA表达、蛋白水平显著低于其他两组,而DNMT1、DNMT3a和HDAC1表达却与SOCS1基因表达呈负相关。SOCS1的甲基化与治疗后完全缓解(complete remission,CR)率呈负相关。药物干预白血病细胞系后,随DNMT1、DNMT3a和HDAC1表达下降和SOCS1基因表达恢复,肿瘤细胞的生长受到抑制。结论:SOCS1基因的甲基化、组蛋白去乙酰化导致基因表达沉默,最终促进急性髓系白血病细胞的生长增殖。

关键词: 急性髓系白血病, 细胞因子信号转导抑制因子1, 甲基化, DNA甲基转移酶1, DNA甲基转移酶3a, 组蛋白去乙酰化酶1

Abstract: Background and purpose: Suppressor of cytokine signaling 1 (SOCS1) is a widely recognized tumor suppressor gene. This study aimed to explore the relationship between the epigenetic modification of SOCS1 gene and acute myeloid leukemia (AML). Methods: We utilized several techniques such as reverse transcription polymerase chain reaction (RT-PCR), methylation-specific PCR (MS-PCR), Western blot, cell culture, drug treatment, cell viability assay and gene knock-out to analyze the expression of SOCS1. We analyzed 110 AML patients treated in the Department of Hematology, Handan Central Hospital, and Department of Hematology, The Second Hospital of Hebei Medical University, from Feb. 2016 to Dec. 2018, and leukemia cell lines U937 and THP-1 to study the underlying molecular mechanism of SOCS1 in AML. We also utilized the changes of DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3a (DNMT3a) and histone deacetylase 1 (HDAC1). Results: We found that SOCS1 gene methylation rate in initial treatment group (IT) and relapsed/refractory group (RR) group was significantly higher than that in remission group (RE) and normal control group (NC) (48% and 80% vs 0% and 0% respectively). Moreover, the mRNA and protein expression were significantly lower in IT and RR when compare to RE and NC. We also found that the expressions of DNMT1, DNMT3a and HDAC1 were negatively affected by SOCS1. SOCS1 methylation was negatively correlated with complete remission (CR) after treatment. After drug treatment, the growth of tumor cells was inhibited with the decrease of DNMT1, DNMT3a and HDAC1 expressions and the recovery of SOCS1 gene expression. Conclusion: SOCS1 gene methylation and deacetylation caused gene silencing of SOCS1 which promoted the growth and proliferation of acute myeloid leukemia cells.

Key words: Acute myeloid leukemia, Suppressor of cytokine signaling 1, Methylation, DNA methyltransferase 1, DNA methyltransferase 3a, Histone deacetylase 1