“抑癌基因”FAT1促进儿童pre-B-ALL急性淋巴细胞白血病对化疗耐受的研究

尽管人非典型钙粘蛋白FAT1在一些肿瘤中起抑癌作用，但我们先期研究发现FAT1在儿童pre-B-ALL中 常呈高表达，并和患者的不良预后有关；siRNA 敲低FAT1导致在接触抑制环境下pre-B-ALL细胞的caspase-8活化和凋亡，并增强pre-B-ALL对长春新碱的敏感性。本研究将利用CRISPR-Cas9敲除FAT1表达的pre-B-ALL细胞株，确认其在促进pre-B-ALL细胞存活及药物耐受的作用、明确其分子机制，并在人pre-B-ALL小鼠移植模型中予以验证；结合临床病理数据确定FAT1高表达和药物治疗pre-B-ALL效果的关系。我们也将明确FAT1在pre-B-ALL细胞中高表达的调控机理。结果有望揭示FAT1在pre-B-ALL通过抑制caspase-8的活化而发挥促癌作用，并为将FAT1作为治疗pre-B-ALL的分子靶点及预测治疗效果的分子标志物提供依据。

The atypical cadherin FAT1 plays a tumor suppressive role in a number of cancer types. However, we have found in preliminary studies that FAT1 is commonly upregulated in childhood pre-B-ALL cells compared with normal peripheral blood lymphocytes and bone marrow cells, and that siRNA knockdown of FAT1 triggered caspase-8 activation and subsequent apoptosis in pre-B-ALL cells grown under contact-inhibition conditions. Moreover, we have found that FAT1 knockdown renders pre-B-ALL cells more sensitive to apoptosis induced by chemotherapeutic drugs. We therefore hypothesize that 1) FAT1 functions as an oncogenic driver and contributes to chemoresistance in pre-B-ALL; 2) FAT1 promotes survival of pre-B-ALL cells under contact-inhibition conditions and upon chemotherapeutic drug treatment through inhibiting caspase-8 activation and 3) high levels of FAT1 expression is predictive of resistance of pre-B-ALL to chemotherapy...In this project, we will clarify the pro-survival role of FAT1 in pre-B-ALL cells and define the mechanism involved. We will confirm the results by use of human pre-B-ALL xenografts in NOD-SCID IL2Rgnull mice. Furthermore, we will determine the transcriptional mechanism responsible for upregulation of FAT1 in pre-B-ALL cells and examine whether the expression of FAT1 is associated with poor prognosis of patients after treatment. The results will define FAT1 as an oncogenic mechanism in pre-B-ALL, in contrast to its tumour suppressive function in other types of cancers, and will provide proof-of-principle for targeting FAT1 in the treatment of pre-B-ALL. Identification of elevated FAT1 as a predictive biomarker of poor outcome of patients will be instructive for developing novel approaches to overcome chemoresistance in pre-B-ALL.