AML1/ETO融合基因通过APP和AML1/ETO9a协同C-KIT基因突变促发白血病的研究

文献报道AML1/ETO融合基因通过AML1/ETO9a协同C-KIT基因突变促发白血病，但是是否需要其他基因参与，尚不清楚。我们已经证实淀粉样前体蛋白（APP）基因在该亚型白血病中高表达且调控髓外浸润。我们的预实验发现APP基因高表达者的C-KIT基因突变显著增加且预后极差；下调APP表达，C-KIT表达下调，细胞凋亡增加。我们推测AML1/ETO融合基因通过APP和AML1/ETO9a协同C-KIT基因突变促发白血病。本课题拟扩大临床病例数验证APP基因与AML1/ETO9a、C-KIT基因突变有关并影响白血病预后，同时采用细胞和动物模型，通过siRNA技术下调APP基因表达，构建基因突变模型和基因敲除等正反相调节干预，探讨APP基因与AML11/ETO9a、C-KIT基因突变的相互关系，进一步阐明AML1/ETO+ 白血病的发病机制，为开发新的治疗靶标提供依据。

It's reported that AML1/ETO fusion gene cooperates with C-KIT mutation to induce leukemia via AML1/ETO9a, however, whether it needs for other genes to involve in, is not clear. We have demonstrated that amyloid precursor protein (APP) gene highly expresses in the subtype leukemia and regulates of extramedullary infiltration. Our preliminary experiments showed that significantly higher incidence of C-KIT mutations and poorer prognosis were observed in the patients with APP high expression; C-KIT expression decreased and cell apoptosis increased when APP expression was downregulated. We speculate that AML1/ETO fusion gene cooperates with C-KIT mutation to induce leukemia via APP and AML1/ETO9a. We intends to expand the number of clinical cases to validate the corelation of APP gene, AML1/ETO9a and C-KIT mutation and the adverse prognostic effect of APP; Moreover, positive and negative regulation is done in cell and murine models, such as downregulating expression of APP by siRNA technology, constructing gene mutation and gene knockout models, to explore the relationship between APP gene and AML11/ETO9a, C-KIT mutation, and then further elucidate the pathogenesis of AML1/ETO-positive leukemia, and provide the basis for new treatment targets development.