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

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。

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

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.