PML基因的砷剂耐药突变对PML核体组装的影响及机制研究

三氧化二砷（ATO）直接靶向PML-RARa癌蛋白使其降解从而达到治愈急性早幼粒细胞白血病（APL）的效果。由于缺乏PML RBCC结构域的结构信息，ATO如何靶向于PML蛋白以及患者出现砷剂耐药的机制目前仍然是一片空白。申请人前期研究揭示了PML蛋白的寡聚化及其在APL发生中的作用，并突破瓶颈首次提纯到包含有RBCC结构域的PML大片段，并解析了一系列PML组装的相关的结构，阐述了核体组装的新机制。本研究将基于前期基础进一步探究PML RBCC结构域的结构信息，进而了解1）ATO如何靶向于PML；2）耐药突变如何影响ATO的靶向；3）进一步明确PML核体动态组装和白血病诊疗的关系。以期为解决临床砷剂耐药问题提供指导、为与PML核体相关的其他白血病的治疗提供方向。

Arsenic trioxide (ATO) has displayed great curative effect in acute promyelocytic leukemia (APL) treatment. Due to the lack of structural information on the RBCC domain of PML, the mechanism of how ATO targets PML protein and why PML muant can evade ATO is poorly understood. Our previous studies revealed an unprecedented oligomerization of PML and its novel role in the pathogenesis of APL, which broke the bottleneck of purifying the large fragment of PML containing the RBCC domain firstly and analyzed a series of PML related structures, revealing a novel mechanism of PML nuclear body assembly. In this study, the structural information of PML nuclear body will be further explored to understand 1) how ATO targets PML RBCC domain; 2) how the drug-resistant mutations affect ATO targeting; 3) how PML dynamic and nuclear body assembly might indluence leukemogenesis and targeted therapy. Altogether, results obtained from this investigation will find therapeutic solution for clinical arsenic drug resistance in leukemia, and offer a direction for the treatment of other leukemia associated with PML NB.