组蛋白伴侣分子ASF1A靶向BCR-ABL依赖和非依赖双重途径驱动慢粒急变的调控机制

慢性粒细胞白血病一旦急变，病情恶化，预后极差；解析慢粒急变的调控机制是重要科学问题。申请者发现组蛋白伴侣分子ASF1A靶向BCR-ABL依赖和非依赖双重途径与慢粒急变发生相关。在此基础上，本项目拟回答的科学问题：ASF1A靶向BCR-ABL依赖和非依赖双重途径驱动慢粒急变的调控机制。综合领域进展和前期研究，凝练出科学假设和拟研究内容：（1）ASF1A通过转录抑制酪氨酸磷酸酶SHP1表达，进而提高具有活性功能的磷酸化BCR-ABL（pBCR-ABL）水平，构成“ASF1A-SHP1-pBCR-ABL调控轴”，以BCR-ABL依赖途径介导慢粒急变；（2）ASF1A被转录因子RBPJ募集共同结合于Notch信号通路靶基因HES1和p21启动子区域，构成“ASF1A/RBPJ-HES1/P21调控轴”，通过BCR-ABL非依赖途径介导慢粒急变；本研究期望发现慢粒急变的新靶点和新机制。

Once chronic myeloid leukemia (CML) transforms into the terminal stage known as blast crisis，the condition quickly worsens and the prognosis is extremely poor. Exploring the underlying mechanism of CML blast crisis is of great significance. The applicant found that histone chaperone ASF1A mediates the blast crisis of CML through both BCR-ABL dependent and independent pathways. Base on this, this project aims to explore scientific questions as follows: the mechanism by which ASF1A mediates CML blast transition through BCR-ABL dependent and independent pathway. Based on progress in this field and the previous research, the scientific hypotheses and proposed research contents are proposed as follows: (1) ASF1A upregulated the phosphorylation of BCR-ABL (pBCR-ABL) by inhibiting the expression of protein phosphatase SHP1 transcriptionally, which mediated CML blast transition by BCR-ABL dependent pathway; (2) Recruited by transcription factor RBPJ, ASF1A and RBPJ co-binds to the promoter region of Notch signaling pathway target genes HES1 and p21, which mediated CML blast transition in a BCR-ABL independent pathway. It is expected to explore innovative targets and new mechanism of CML blast transition.