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

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.

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。

AML1/ETO+白血病的发病模式是白血病“二次打击”学说最好的诠释。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。本课题组在前期研究中已经证实APP基因在AML1/ETO+ AML中高表达且与髓外浸润相关。本课题通过临床病历和细胞株研究明确APP基因与AML1/ETO9a、C-KIT突变的关系以及对白血病预后的影响，进而通过动物模型体内验证，进一步阐明AML1/ETO+ 白血病的发病机制。通过本课题研究，证实了APP基因与C-KIT突变有关，APP协同C-KIT突变上调c-kit表达异常激活PI3K/AKT通路进而抑制AML1/ETO+白血病细胞的凋亡，影响疾病预后，进一步解释C-KIT突变在AML1/ETO+白血病中高发生的原因及阐明该白血病的发病机制，为开发APP作为新的治疗靶标提供依据；证实APP高表达是预后的独立不良因素，定量检测APP表达可以预测疾病预后，可作为分层诊治的重要指标，获得国家发明专利一项。利用二代测序检测了患者初发病和复发时的基因突变特征，进一步明确了该白血病的基因突变谱，分析不同基因突变对预后的影响及复发时分子克隆演变情况，首次建立了预后分层积分体系，指导精准诊治，已经开展多中心前瞻性临床研究。我们的研究结果多次在ASH展示，获得广东省论文比赛一等奖；另外研究论文在Oncology Reports、Tumor & Biol、Neoplasma、Oncology Letters等杂志发表。后续研究获得南方医科大学临床研究育苗项目、南方医院院长项目、南方医科大学创新驱动培育项目等资助。

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