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浙江大学学报（医学版）
浙江大学学报（医学版）  2018, Vol. 47 Issue (5): 541-551    DOI: 10.3785/j.issn.1008-9292.2018.10.15
综述     
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
郝睿1,2(),苏力德1,2,邵一鸣1,2,部娜3,马丽亚4,那仁满都拉1,2,4,5,*()
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
Involvement of PML proteins in treatment of acute promyelocytic leukemia with arsenic trioxide
HAO Rui1,2(),SU Lide1,2,SHAO Yiming1,2,BU Na3,MA Liya4,NARANMAN DURAHua1,2,4,5,*()
1. Department of Pharmacology, Inner Mongolia Medical University, Hohhot 010000, China
2. School of Medicine and Public Health, Zhejiang University, Hangzhou 310058, China
3. Department of Pharmacy, Woman's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
4. Department of Hematology, the First Affiliate Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
5. Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China
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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、PML-RARα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。
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    
Abstract:

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.
Key words: Leukemia, promyelocytic, acute/drug therapy    Arsenicals/therapeutic use    Neoplasm proteins/biosynthesis    Small ubiquitin-related modifier proteins/genetics
收稿日期: 2018-07-20 出版日期: 2019-01-23
:  R733.71  
基金资助: 国家自然科学基金(81473289, 81673521, 81603125, 81600139)
通讯作者: 那仁满都拉     E-mail: hao61977@163.com;narenman@zju.edu.cn
作者简介: 郝睿(1993-), 女, 硕士研究生, 主要从事砷剂治疗急性早幼粒细胞白血病的机制研究; E-mail:hao61977@163.com; https://orcid.org/0000-0002-9700-1434
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引用本文:

郝睿,苏力德,邵一鸣,部娜,马丽亚,那仁满都拉. 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[J]. 浙江大学学报（医学版）, 2018, 47(5): 541-551.

HAO Rui,SU Lide,SHAO Yiming,BU Na,MA Liya,NARANMAN DURAHua. Involvement of PML proteins in treatment of acute promyelocytic leukemia with arsenic trioxide. J Zhejiang Univ (Med Sci), 2018, 47(5): 541-551.

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http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2018.10.15    或    http://www.zjujournals.com/med/CN/Y2018/V47/I5/541

图 1  早幼粒细胞白血病(PML)各亚型结构示意图
PML亚型 功能
PML-Ⅰ 促进骨髓细胞的分化[24]；与单纯疱疹病毒1型早期蛋白ICP0连接，该蛋白具有E3泛素连接酶功能域，使PML-Ⅰ型蛋白可通过ICP0降解[25-26]
PML-Ⅱ 特异性抑制脊髓小脑共济失调Ⅲ蛋白(ATXN3)去泛素酶活性, 拮抗ATXN3对PML核小体的干扰[27]；5型腺病毒通过作用于PML-Ⅱ型蛋白外显子7b，提高病毒的转录水平，干扰PML核小体形成[28]
PML-Ⅲ 抑制有丝分裂激酶极光激酶A，调控细胞中心体的复制[29]
PML-Ⅳ 保护细胞免受狂犬病毒、水痘-带状疱疹病毒、脑心肌炎病毒等感染[30-32]；在PML核小体中，PML-Ⅳ型蛋白通过招募并激活P53蛋白，从而促进细胞凋亡及衰老[33-35]
PML-Ⅴ 可能是构成PML核小体的主要骨架蛋白，并通过其羧基端的第591~611位氨基酸招募死亡结构域相关蛋白、SP100等相关蛋白形成核小体[36]
PML-Ⅵ 由于其在外显子7a部分缺乏SUMO相互作用基序(SIM)结构，致使PML-Ⅵ型蛋白表现出对三氧化二砷有抗性[22, 37]，但也有报道指出PML-Ⅵ可被三氧化二砷完全降解，因此该亚型的功能有待进一步考证
PML-Ⅶ 在细胞因子信号转导[38]、细胞凋亡[39]、病毒防御方面发挥重要作用[40]
表 1  早幼粒细胞白血病(PML)蛋白各亚型及其功能
图 2  不同早幼粒细胞白血病-维甲酸受体α(PML-RARα)融合蛋白结构示意图
图 3  三氧化二砷作用于早幼粒细胞白血病(PML)蛋白部分示意图
图 4  相关功能蛋白与早幼粒细胞白血病(PML)蛋白通过SUMO相结合
图 5  早幼粒细胞白血病(PML)蛋白SUMO化过程
图 6  PML-RARα点突变干扰三氧化二砷诱导PML-RARα蛋白降解示意图
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