RUNX3增强C/EBPα转录促进白血病干细胞衰老的作用机制研究

白血病耐药复发是制约治疗效果的难题，白血病干细胞（LSCs）抗衰老和对化疗不敏感是导致白血病耐药复发的主要原因。我们前期研究表明RUNX3在白血病细胞中缺失或低表达，其表达与白血病患者的治疗效果呈正相关；外源高表达RUNX3可通过上调C/EBPα的表达，促进白血病细胞的衰老，逆转耐药。因此，我们提出克服白血病干细胞耐药的新机制：RUNX3增强C/EBPα启动子的转录活性，C/EBPα表达增加，进而促进LSCs衰老。本课题拟通过细胞转录模型、FLT3-ITD介导的白血病小鼠模型，明确RUNX3-C/EBPα与LSCs衰老的关系及分子机理，并采用临床标本分析RUNX3-C/EBPα作为预示白血病疾病进程及耐药复发标志物的可行性。本课题将阐明RUNX3-C/EBPα通路与LSCs衰老的关系，为临床治疗白血病以及克服耐药复发提供新策略。

Drug resistance and recurrence is the limitation for leukemia treatment. Our previous study showed that leukemic stem cells (LSCs) induced drug resistance. In addition, leukemia patients expressed low level of RUNX3 and displayed worse outcomes, while RUNX3 overexpression led to leukemic cell apoptosis，overcame drug resistance. Importantly, RUNX3 overexpression induced cell senescence by inducing C/EBPα expression at transcriptional level. The aim of this project is to investigate the role of RUNX3-C/EBPα in LSCs senescence by cell model and leukemia animal model, and further confirm by clinical leukemia samples. This project will reveal the underline molecular mechanism of RUNX3-C/EBPα in LSCs senescence, and investigate the possibility of RUNX3-C/EBPα acting as a new biomarker in leukemia treatment.