DNA/RNA双重结合候选蛋白Lin28B转录和转录后共激活BCR/ABL促进慢粒急变的调控机制

Once chronic myelogeous leukemia (CML) transforms into the terminal stage known as blastic phase (BP), the disease becomes highly aggressive and incurable. Although the mechanisms underlying CML-BP is heterogeneous and complex, the uncontrollable activation of BCR/ABL is considered to be a key driving force of CML blast crisis. The applicant found that Lin28B is a marker indicating the blast crisis transition. Preliminary study showed that Lin28B is a candidate of DNA- and RNA- binding proteins (DRBPs) and might activate BCR/ABL transcriptionally and post-transcriptionally. Given that transcriptional and post-transcriptional regulation determines human gene expression pattern and the development and progression of disease together, in views of the scientific frontiers and preliminary study, the applicant aimed to explore the scientific problems as follows: (1) Molecular and cellular level: Confirm the biological functional properties of Lin28B as DRBPs and the regulatory network mechanisms of BCR/ABL cascade activation at transcriptional and post-transcriptional level. (2) Animal level: Evaluate the role of Lin28B inhibition involved in BCR/ABL regulation and the anti-leukemia effect. (3) Human specimen level: Validate the correlation between Lin28B and BCR/ABL and the blast transformation in CML-BP patients. By research, this study aims to find the new mechanisms and targets of CML blast crisis transition based on Lin28B.

慢性粒细胞白血病（简称：慢粒）一旦急变，病情凶险，尽管机制复杂，高度异质，但是BCR/ABL失控性激活被认为是慢粒急变的驱动力。申请者发现Lin28B是慢粒急变跨越的标志分子，前期研究提示Lin28B是DNA/RNA双重结合蛋白（DRBPs）候选分子，可能在转录和转录后水平共激活BCR/ABL。鉴于转录和转录后调控决定着人类基因表达模式和疾病发生发展规律，综合科学前沿和前期研究，申请者凝练出主要研究内容：（1）分子细胞层面：确定Lin28B作为 DNA/RNA双重结合蛋白的生物学功能属性，及其在转录和转录后水平共激活BCR/ABL的调控机制；（2）整体动物层面：评估干预Lin28B 对BCR/ABL调控功能和抗白血病细胞效应的影响； （3）人体组织层面：验证慢粒急变患者Lin28B对BCR/ABL的调控状况与疾病程度的关联性。通过上述研究，明确基于Lin28B的慢粒急变新机制和新靶点。

慢性粒细胞白血病（简称：慢粒）一旦急变，病情凶险，尽管机制复杂，高度异质，但是BCR/ABL失控性激活被认为是慢粒急变的驱动力。申请者发现Lin28B是慢粒急变跨越的标志分子，前期研究提示Lin28B是DNA/RNA双重结合蛋白（DRBPs）候选分子，可能在转录和转录后水平共激活BCR/ABL。鉴于转录和转录后调控决定着人类基因表达模式和疾病发生发展规律，综合科学前沿和前期研究，申请者凝练出主要研究内容：（1）分子细胞层面：确定Lin28B作为 DNA/RNA双重结合蛋白的生物学功能属性，及其在转录和转录后水平共激活BCR/ABL的调控机制；（2）整体动物层面：评估干预Lin28B对BCR/ABL调控功能和抗白血病细胞效应的影响；（3）人体组织层面：验证慢粒急变患者Lin28B对BCR/ABL的调控状况与疾病程度的关联性。通过上述研究，明确基于Lin28B的慢粒急变新机制和新靶点。