PML等位基因突变介导急性早幼粒细胞白血病患者对三氧化二砷耐药的分子机制研究

三氧化二砷（ATO）是目前临床上治疗急性早幼粒细胞白血病（APL）的一线药物，通过特异性降解PML/RARα（P/R）融合蛋白达到治疗疾病的目的。然而，临床上仍然有部分APL患者出现ATO耐药现象，无有效治疗手段，预后差，死亡率高。新英格兰医学杂志报道，除了 P/R基因外，同源染色体中未融合的等位基因PML发生错义突变也会导致ATO耐药，但其作用机制仍然未知。本课题前期结果显示，等位基因编码的正常PML蛋白能够通过招募p62蛋白入核形成PML-p62-P/R复合体并增强其泛素化，进而促进P/R融合蛋白的降解。而等位基因PML突变后所编码的蛋白突变体则会通过干扰上述过程抑制P/R融合蛋白的降解。本课题拟采用毒理学、分子生物学等技术和方法探究正常PML蛋白参与ATO降解P/R融合蛋白的分子机制，进一步阐明ATO的耐药机理，从而对诊断方式的变更、治疗方案的选择、新靶点的发现具有重要的临床意义。

Nowadays, arsenic trioxide (ATO) are the first-line drug for clinical treatment of acute promyelocytic leukemia (APL). It could cure APL by specifically degrading PML-RARα (P/R) oncogenic fusion protein. However, most relapsed APL patients develop arsenic resistance, while the therapeutic strategy after relapse has relatively poor outcomes, less effective, and high mortality rate. The New England Journal of Medicine reported that arsenic resistance was caused by the genetic mutations in PML allele apart from those in P/R, but the mechanism of resistance at PML allele mutation remains unknown. The preliminary results of our research demonstrated that wild-type PML protein encoded by PML allele can recruit the SQSTM-1/p62 protein into the nucleus and form a PML-p62-P/R complex. p62 protein enhanced the ubiquitination of the complex and promoted ATO-induced degradation of P/R fusion protein. Nevertheless, the mutant protein encoded by the mutated PML allele inhibited the degradation of the P/R fusion protein by interfering the normal circumstances. This project intends to explore the molecular mechanism of the involvment of PML protein in ATO-induced P/R fusion protein degradation through the basis of pharmacology and molecular biology. Further, the ATO resistance mechanism that caused by PML allele mutation was clarified. Our research provided the evidence for the promotion of diagnostic methods, treatment plans and discovery of new targets which are clinically significant.