砷剂已被广泛应用于治疗急性早幼粒白血病（APL）。然而，在治疗过程中部分患者出现砷剂耐药现象，其原因由于PML蛋白的B-box2结构域上发生点突变，导致砷剂无法诱导上述PML/RARα(P/R)突变体的溶性改变，使其无法进一步降解，故而产生耐药。我们首次发现单用热激（43°C）不仅能够诱导野生型P/R蛋白的降解，还能够使得砷剂耐药的所有P/R突变体的降解。我们还发现RARα部分的LBD结构域是热激诱导P/R融合蛋白溶性转变及降解的关键性区域。有趣的是，虽然砷剂不能诱导P/R突变体的溶性改变，但是热激与砷剂联用可增强P/R突变体的SUMO化及Ub修饰，加速其降解。本项目通过研究热激降解砷剂耐药P/R融合蛋白，明确回答以下三个问题：明确热激诱导P/R蛋白的降解的作用位点；确定参与热激反应的关键蛋白及其功能和生理学意义；揭示热激与砷剂协同作用的分子机理，有望用于治疗APL患者（包括砷剂耐药）。

Arsenic trioxide (As2O3) has been world widely used to treat acute promyelocytic leukemia (APL), and PML-RARα onco-fusion protein solubility changes, followed by SUMOylation and degradation by arsenic are considered to be the key process for APL treatment. Unfortunately, As2O3-resistance patients are frequently found in relapsed APL after consolidation therapy, which are considered to be associated with missense mutations in B-box2 domain of PML-RARα (P/R) fusion protein. In this project, we for the first time identified that heat treatment (43°C) not only induce wild type P/R fusion protein degradation, but also induce missense mutants P/R fusion protein degradation. Additionally, we found that ligand binding domain (LBD) of RARα portion is responsible for PML-RARα fusion protein degradation by heat treatment. More interestingly, although arsenic alone is unable to induce the mutants P/R fusion protein degradations, combination of heat treatment with As2O3 significantly increase the P/R fusion protein SUMOylation and ubiquitination as well as facilitate its protein degradation. The extraordinary characteristics of heat treatment in both wild type and missense mutants P/R fusion protein solubility changes and/or degradations makes us enthusiastic to identify the probable mechanism of action of heat treatment in APL therapy. Therefore, in the current project we are trying to resolve the following issues, i.e., (1) to clarify the exact action site of P/R protein that responsible for protein degradation by heat treatment; (2) to identify what kind of nuclear proteins are involved in P/R protein solubility changes and degradation as well as its functional and physiological significances; (3) how combination of heat treatment with As2O3 could facilitate its mutant P/R protein degradation or solubility changes? Thus, this project will helpful to improve therapeutic strategies for newly diagnosed and arsenic-resistance APL in near future.