染色质调控因子ASXL1影响中性粒细胞发育的机制研究

染色质调控因子ASXL1是髓系恶性肿瘤最常见的突变基因之一，大约占各类病人的5%-48%，而其发病机制并不明确。我们的前期工作发现：① 斑马鱼Asxl1截短突变所导致的中性粒细胞发育不良可能作为髓系恶性肿瘤的发病基础；② Asxl1可能特异性调节中性粒细胞相关基因表达；③ Asxl1羧基端缺失增强了自身蛋白稳定性。但仍有以下问题亟待解决：① Asxl1调节中性粒细胞发育的哪个阶段；② Asxl1调节中性粒细胞相关调控因子表达的作用机制？我们假设：① Asxl1羧基端截短突变可能特异性抑制中性粒细胞成熟；② Asxl1羧基端功能域缺失可能改变其识别的染色质状态及所结合蛋白成分或功能，进而导致中性粒细胞相关调控因子表达的异常。藉此本项目拟研究Asxl1羧基端缺失突变后导致中性粒细胞发育异常的机制，以期为临床治疗髓系恶性肿瘤提供可能的线索。

ASXL1 is one of the most frequently mutated genes in malignant myeloid diseases (5%-48%). Current disease models cannot fully recapitulate leukemogenesis and disease progression. We generated an endogenous C-terminal-truncated Asxl1 mutant in zebrafish that perturbs neutrophil differentiation. ① Our model demonstrated that neutrophilic dysplasia caused by asxl1 mutation is a foundation for the progression of myeloid malignancies. ② Asxl1 may specifically regulate the expression of neutrophil differentiation regulator. ③ Truncated Asxl1 is more stable than wildtype Asxl1. However, it is unclear ① which stage is the specific perturbing stage of neutrophil differentiation in asxl1 mutants; ② how Asxl1 regulates the expression of neutrophil differentiation regulator. Our hypothesis is that ① Asxl1 C-terminal mutation perturbing neutrophil maturation; ② the change of chromatin state and its interaction partner of ASXL1 after C-terminal mutation will lead to the dysregulation of the expression of neutrophil differentiation regulator. This study can help us to reveal the mechanism of neutrophilic dysplasia after Asxl1 mutation and find potential therapeutic target of myeloid malignancies.