Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL
文献类型：期刊论文
| 作者 | Li, BS; Li, H; Bai, Y; Kirschner-Schwabe, R; Yang, JJ; Chen, Y; Lu, G; Tzoneva, G; Ma, XT; Wu, TM |
| 刊名 | NATURE MEDICINE
 |
| 出版日期 | 2015 |
| 卷号 | 21期号:6页码:563-571 |
| 通讯作者 | Zhou, BBS (reprint author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr,Minist Hlth, Dept Hematol & Oncol,Key Lab Pediat Hematol & Onc, Shanghai 200030, Peoples R China.,tangingyan@scmc.com.cn ; wangsy@chgc.sh.cn ; binbing_s_zhou@yahoo.com |
| 英文摘要 | Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL. |
| 学科主题 | Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine |
| 类目[WOS] | Biochemistry & Molecular Biology ; Cell Biology ; Medicine, Research & Experimental |
| 关键词[WOS] | ACUTE LYMPHOBLASTIC-LEUKEMIA ; PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY ; NOVO NUCLEOTIDE BIOSYNTHESIS ; CANCER ; CHILDREN ; PURIFICATION ; MUTATIONS ; ENZYME ; FIBROBLASTS ; METABOLISM |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000355778300012 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/73]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Li, BS,Li, H,Bai, Y,et al. Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL[J]. NATURE MEDICINE,2015,21(6):563-571. |
| APA | Li, BS.,Li, H.,Bai, Y.,Kirschner-Schwabe, R.,Yang, JJ.,...&Zhou, BBS.(2015).Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.NATURE MEDICINE,21(6),563-571. |
| MLA | Li, BS,et al."Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL".NATURE MEDICINE 21.6(2015):563-571. |
入库方式： OAI收割
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。