PML蛋白参与三氧化二砷治疗急性早幼粒细胞白血病的分子生物学机制研究  

Involvement of PML proteins in treatment of acute promyelocytic leukemia with arsenic trioxide

作　　者：郝睿 苏力德 邵一鸣 部娜[3] 马丽亚[4] 那仁满都拉 HAO Rui;SU Lide;SHAO Yiming;BU Na;MA Liya;NARANMANDURA Hua(Department of Pharmacology,Inner Mongolia Medical University,Hohhot 010000,China;School of Medicine and Public Health,Zhejiang University,Hangzhou 310058,China;Department of Pharmacy,Woman's Hospital,Zhejiang University School of Medicine,Hangzhou 310006,China;Department of Hematology,the First Affiliate Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China;Department of Pharmacology,Zhejiang University School of Medicine,Hangzhou 310058,China)

机构地区：[1]内蒙古医科大学药学院药理教研室,内蒙古呼和浩特010000 [2]浙江大学医学院公共卫生学院,浙江杭州310058 [3]浙江大学医学院附属妇产科医院药剂科,浙江杭州310006 [4]浙江大学医学院附属第一医院血液科,浙江杭州310003 [5]浙江大学医学院药理研究所,浙江杭州310058

出　　处：《浙江大学学报（医学版）》2018年第5期541-551,共11页Journal of Zhejiang University(Medical Sciences)

基　　金：国家自然科学基金(81473289;81673521;81603125;81600139)

摘　　要：PML蛋白作为一种肿瘤抑制因子,在三氧化二砷治疗急性早幼粒细胞白血病(APL)的过程中发挥重要作用。绝大多数APL患者的典型特征是细胞内PML基因和RARα基因发生融合,该融合基因所表达的PML-RARα融合蛋白是APL发病的主要原因。三氧化二砷作为临床治疗APL的一线药物,通过直接作用于PML-RARα融合蛋白的PML部分,诱导相关蛋白多聚化,并招募多种功能蛋白,促进PML核小体重构,使PML-RARα蛋白发生小泛素修饰蛋白(SUMO)化和泛素化,最终经蛋白酶体途径降解,达到治疗APL的目的。PML蛋白发生点突变会导致APL复发及三氧化二砷耐药。本文阐述了PML蛋白的结构和功能、PMLRARα融合蛋白诱导APL发病的机制、PML蛋白参与三氧化二砷治疗APL的分子机制以及PML蛋白发生突变导致APL患者发生三氧化二砷耐药的现象,以期为目前治疗方案的优化及针对耐药患者有效治疗手段的开发提供理论指导。Promyelocytic leukemia(PML) protein,a tumor suppressor,plays an important role in patients with acute promyelocytic leukemia(APL) receiving arsenic trioxide(As2O3) therapy.APL is a M3 subtype of acute myeloid leukemia(AML),which is characterized by expression of PML-RARα(P/R) fusion protein,leading to the oncogenesis.As2O3 is currently used as the first-line drug for patients with APL,and the mechanism may be:As2O3 directly binds to PML part of P/R protein and induces multimerization of related proteins,which further recruits different functional proteins to reform PML nuclear bodies(PML-NBs),and finally it degraded by SUMOylation and ubiquitination proteasomal pathway.Gene mutations may lead to relapse and drug resistance after As2O3 treatment.In this review,we discuss the structure and function of PML proteins;the pathogenesis of APL induced by P/R fusion protein;the involvement of PML protein in treatment of APL patient with As2O3;and explain how PML protein mutations could cause resistance to As2O3 therapy.

关 键 词：白血病 早幼粒细胞 急性/药物疗法 砷剂/治疗应用 肿瘤蛋白质类/生物合成 小泛素相关修饰蛋白质类/遗传学 

分 类 号：R733.71[医药卫生—肿瘤]