ZCCHC10通过调控p53和CXCL12/CXCR4轴抑制急性髓系白血病的机制研究

P53失活和CXCL12/CXCR4轴的过度激活均可促进急性髓系白血病（AML）发生发展。申请者前期研究发现ZCCHC10可以抑制MDM2介导的p53泛素化降解，并通过上调CCL18和下调CXCL12来抑制CXCR4的激活。发现lncRNA SNHG1通过促进ZCCHC10启动子甲基化抑制其表达。在AML细胞和AML异种移植小鼠上证实过表达ZCCHC10抑制AML进展。据此推测：ZCCHC10通过激活p53和抑制CXCL12/CXCR4轴来抑制AML发生发展，而SNHG1介导ZCCHC10甲基化沉默是AML发生发展的驱动因素。本项目拟在临床样本、细胞水平和小鼠模型(包括AML异种移植小鼠和基因敲除小鼠）上探究ZCCHC10在AML发生发展中的作用和分子机制以及ZCCHC10在AML中表达下调的分子机制。期望获得AML的一个新的抑癌基因，为AML提供新的诊断和预后判断的标志物和治疗靶点。

Both inactivation of p53 and overactivation of CXCL12 / CXCR4 axis can promote the development of acute myeloid leukemia (AML). The applicant's previous research found that ZCCHC10 can inhibit MDM2-mediated p53 ubiquitination degradation and inhibit CXCR4 activation by up-regulating CCL18 and down-regulating CXCL12. It was found that lncRNA SNHG1 inhibited its expression by promoting methylation of ZCCHC10 promoter. ZCCHC10 overexpression was demonstrated to inhibit AML progression in AML cells and AML xenograft mice. Based on this, we speculated that ZCCHC10 inhibits the occurrence and development of AML by activating p53 pathway and inactivating CXCL12 / CXCR4 axis, whereas epigenetically silencing ZCCHC10 by SNHG1 is the driving factor for the development of AML. This project intends to explore the role and molecular mechanism of ZCCHC10 in the occurrence and development of AML through analysis of clinical samples, combined with cytology experiments, AML xenograft mouse models and gene knockout mouse models. These studies will find a novel tumor suppressive gene of AML, and supply a novel molecular marker of diagnosis and prognosis and therapeutic target for AML.