负反馈调控的缺失--一个由PRPS1基因突变而引起的巯基嘌呤耐药在儿童急性淋巴细胞性白血病的复发

摘要：

白血病复发是儿童急性淋巴细胞性白血病致死的主要原因,然而截止到目前白血病的复发耐药机制仍然还不清楚.众所周知,在所有化疗白血病的药物中6巯基嘌呤是最常用的一种化疗药物.本研究采用外显子捕获技术,对16组病人的初发、缓解、复发样本进行检测,共发现373个潜在的有义基因突变位点(Non-silent SNV),其中与嘌呤代谢相关的PRPS1基因在多个样本中均检测到有复发特异性的突变.为了进一步验证我们的发现,在134例中国的样本和220例德国的样本进行验证,发现有24个样本都出现了PRPS1的基因突变.进一步深度测序,发现多数突变都产生在复发的早期,从而提示该基因可能为白血病复发的始动基因.通过功能分析这些基因突变,发现这些突变克隆可能是通过减弱ADP对PRPS1的负反馈抑制,从而导致嘌呤从头合成途径增强,次黄嘌呤核苷酸等代谢产物增多,最终抑制6巯基嘌呤代谢相关基因HGPRT1与药物的结合.除此之外,本研究还发现嘌呤从同合成途径的抑制剂洛美曲索可以有效抑制由PRPS1基因突变而引起的耐药.以上研究结果首次揭示了嘌呤从头合成途径在6巯基嘌呤耐药中的作用,为将来有效治疗白血病的复发创造条件.

关键词： 儿童急性淋巴细胞性白血病 疾病复发 病理机制 基因突变 巯基嘌呤耐药

作者: Benshang Li Hui Li Yun Bai Renate Kirschner-Schwabe Jun J Yang Yao Chen Gang Lu Gannie Tzoneva Xiaotu Ma Tongmin Wu Wenjing Li Haisong Lu Lixia Ding Huanhuan Liang Xiaohang Huang Minjun Yang Lei Jin Hui Kang Shuting Chen Alicia Du Shuhong Shen Jianping Ding Hongzhuan Chen Jing Chen Arend won Stackelberg Longjun Gu Jinghui Zhang Adolfo Ferrando Jingyan Tang Shengyue Wang Bin-Bing S Zhou

作者单位: Key Laboratory of Pediatric Hematology and Oncology Ministry of Health,Department of Hematology and Key Laboratory of Pediatric Hematology and Oncology Ministry of Health,Department of Hematology and Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese N Department of Pediatric Oncology and Hematology, Charité-Universit(a)tsmedizin Berlin, Berlin, Germa St.Jude Children”s Research Hospital, Memphis, Tennessee, USA Key Laboratory of Pediatric Hematology and Oncology Ministry of Health,Department of Hematology and Institute for Cancer Genetics, Columbia University, New York, New York, USA National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute o 10 ChemPartner Co., Shanghai, China Key Laboratory of Pediatric Hematology and Oncology Ministry of Health,Department of Hematology and Department of Pharmacology, School of Basic Medicine and Collaborative Innovation Center for Transla Department of Pediatric Oncology and Hematology, Charité-Universit(a)tsmedizin Berlin, Berlin, Germa Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese N Key Laboratory of Pediatric Hematology and Oncology Ministry of Health,Department of Hematology and

会议类型: 国内会议

会议名称: 2016全国博士后学术论坛

会议地点: 上海

会议语种:中文

页码: 69-84

在线出版日期: 2015-09-24（万方平台首次上网日期，不代表论文的发表时间）