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Nat Med. 2015 Jun;21(6):563-71. doi: 10.1038/nm.3840. Epub 2015 May 11.

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

Author information

1
1] Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China. [3] Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
1] Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [3] Department of Pharmacology, School of Basic Medicine and Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3
Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
4
1] Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany. [2] German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
5
St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
6
1] Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
7
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
8
National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
9
ChemPartner Co., Shanghai, China.
10
Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
11
1] Department of Pharmacology, School of Basic Medicine and Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Collaborative Innovation Center of Systems Biomedicine, National Research Center for Translational Medicine, Shanghai, China.
12
Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
13
1] Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China. [2] Collaborative Innovation Center of Systems Biomedicine, National Research Center for Translational Medicine, Shanghai, China.
14
1] Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2] Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [3] Department of Pharmacology, School of Basic Medicine and Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [4] Collaborative Innovation Center of Systems Biomedicine, National Research Center for Translational Medicine, Shanghai, China.

Abstract

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.

PMID:
25962120
PMCID:
PMC4670083
DOI:
10.1038/nm.3840
[Indexed for MEDLINE]
Free PMC Article

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