Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL

被引：133

作者：

Li, Benshang ^{[1
,2
,3
]}

Li, Hui ^{[1
,3
,4
,5
]}

Bai, Yun ^{[2
]}

Kirschner-Schwabe, Renate ^{[6
,7
]}

Yang, Jun J. ^{[8
]}

Chen, Yao ^{[1
,3
]}

Lu, Gang ^{[2
]}

Tzoneva, Gannie ^{[9
]}

Ma, Xiaotu ^{[8
]}

Wu, Tongmin ^{[1
,3
,4
,5
]}

Li, Wenjing ^{[10
]}

Lu, Haisong ^{[11
]}

Ding, Lixia ^{[1
,3
]}

Liang, Huanhuan ^{[1
]}

Huang, Xiaohang ^{[1
]}

Yang, Minjun ^{[2
]}

Jin, Lei ^{[2
]}

Kang, Hui ^{[2
]}

Chen, Shuting ^{[2
]}

Du, Alicia ^{[11
]}

Shen, Shuhong ^{[1
,3
]}

Ding, Jianping

Chen, Hongzhuan ^{[4
,5
,12
]}

Chen, Jing ^{[1
]}

von Stackelberg, Arend ^{[6
]}

Gu, Longjun ^{[1
]}

Zhang, Jinghui ^{[8
]}

Ferrando, Adolfo ^{[9
]}

Tang, Jingyan ^{[1
]}

Wang, Shengyue ^{[2
,12
]}

Zhou, Bin-Bing S. ^{[1
,3
,4
,5
,12
]}

机构：

[1] 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

[2] Chinese Natl Human Genome Ctr Shanghai, Key Lab Hlth & Dis Genom, Shanghai Minist Sci & Technol, Shanghai 200030, Peoples R China

[3] Shanghai Jiao Tong Univ, Sch Med, Pediat Translat Med Inst, Shanghai 200030, Peoples R China

[4] Shanghai Jiao Tong Univ, Sch Med, Sch Basic Med, Dept Pharmacol, Shanghai 200030, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Collaborat Innovat Ctr Translat Med, Shanghai 200030, Peoples R China

[6] Charite, Dept Pediat Oncol & Hematol, D-13353 Berlin, Germany

[7] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany

[8] St Jude Childrens Res Hosp, Memphis, TN 38105 USA

[9] Columbia Univ, Inst Canc Genet, New York, NY USA

[10] Chinese Acad Sci, Natl Ctr Prot Sci Shanghai, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai, Peoples R China

[11] ChemPartner Co, Shanghai, Peoples R China

[12] Natl Res Ctr Translat Med, Collaborat Innovat Ctr Syst Biomed, Shanghai, Peoples R China

来源：

NATURE MEDICINE | 2015年 / 21卷 / 06期

基金：

中国博士后科学基金; 中国国家自然科学基金; 美国国家卫生研究院;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY; NOVO NUCLEOTIDE BIOSYNTHESIS; CANCER; CHILDREN; PURIFICATION; MUTATIONS; ENZYME; FIBROBLASTS; METABOLISM;

D O I：

10.1038/nm.3840

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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.

引用

页码：563 / 571

页数：9

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