低剂量索拉非尼联合全反式维A酸诱导野生型Fms样酪氨酸激酶3的急性髓系白血病细胞分化  

Low-dose sorafenib combined with all-trans retinoic acid induces differentiation of acute myeloid leukemia cells with wild type Fms like tyrosine kinase 3

作　　者：卢昊 奚会民 李璐 蔡循[1] LU Hao;XI Huimin;LI Lu;CAI Xun(Shanghai Institute of Hematology,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;Department of Hematology,Shanghai Sixth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200233,China)

机构地区：[1]上海交通大学医学院附属瑞金医院上海血液学研究所,上海200025 [2]上海交通大学医学院附属第六人民医院血液科,上海200233

出　　处：《内科理论与实践》2022年第6期428-434,共7页Journal of Internal Medicine Concepts & Practice

基　　金：上海市科学技术委员会科研计划项目(项目编号:17ZR1417100)。

摘　　要：目的:研究低剂量索拉非尼与全反式维A酸(all-trans retinoic acid,ATRA)联合,对野生型Fms样酪氨酸激酶3(Fms like tyrosine kinase3,FLT3)的急性髓系白血病(acute myeloid leukemia,AML)细胞的效应及机制。方法:以野生型FLT3的AML细胞系HL-60、U937以及ATRA耐药的HL-60细胞系——HL-60Res为体外模型,以细胞表面分化抗原CD11b和形态学观察评估细胞分化;应用蛋白质印迹法研究Raf蛋白激酶、促分裂原活化的蛋白激酶(mitogenactivated protein kinase,MEK)和胞外信号调节激酶(extracellular signal-regulated kinase,ERK)的活化状态、PU.1、C/增强子结合蛋白(enhancer-binding protein,EBP)β和C/EBPε的蛋白含量。结果:低剂量(0.1~0.5μmol/L)索拉非尼促进ATRA诱导HL-60、U937和HL-60Res 3株细胞系分化。两药联合活化Raf、MEK和ERK,并上调PU.1、C/EBPβ和C/EBPε的蛋白含量,MEK的特异性抑制剂曲美替尼可抑制两药诱导的细胞分化、MEK/ERK活化以及PU.1、C/EBPβ和C/EBPε的蛋白含量上调。结论:索拉非尼与ATRA联合,通过Raf/MEK/ERK通路上调PU.1、C/EBPβ和C/EBPε的蛋白含量,诱导野生型FLT3的AML细胞分化。Objective To explore the effect and the mechanisms of the combination of low-dose sorafenib and all-tran retinoic acid(ATRA)in acute myeloid leukemia(AML)cells with wild type Fms like tyrosine kinase 3(FLT3).Methods The wild type FLT3 AML cell lines HL-60,U937 and the ATRA-resistant HL-60 cell line,HL-60Res were used as in vitro models.The cell differentiation was evaluated with cell surface differentiation antigen CD11b and cellular morphology.The activation of Raf,mitogenactivated protein kinase(MEK)and extracellular signal-regulated kinase(ERK),the protein expression levels of PU.1,C/EBPβand C/EBPεwere measured by Western blotting assay.Results Low dose(0.1~0.5μmol/L)sorafenib enhanced ATRA-induced differentiation in all three cell lines studied.The combination activated Raf,MEK and ERK,and up-regulated the levels of C/EBPβ,C/EBPεand PU.1.Addition of trametinib,a MEK specific inhibitor,suppressed the differentiation induced by sorafenib and ATRA,preventing the activation of MEK/ERK and up-regulation of the levels of C/EBPβ,C/EBPεand PU.1.Conclusions The combination of low-dose sorafenib and ATRA induced differentiation of AML cells with wild type FLT3 via RAF/MEK/ERK-mediated up-regulation of the protein levels of C/EBPβ,C/EBPεand PU.1.

关 键 词：索拉非尼 全反式维A酸 细胞分化 急性髓系白血病 

分 类 号：R733.71[医药卫生—肿瘤]