title: Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.
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.
authors.affiliation: 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.
authors.forename: Benshang
authors.initials: B
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: 1] Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany. [2] German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Renate
authors.identifier: 0000000163353274
authors.initials: R
authors.lastname: Kirschner-Schwabe
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Gannie
authors.initials: G
authors.lastname: Tzoneva
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Xiaotu
authors.initials: X
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Tongmin
authors.initials: T
authors.lastname: Wu
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.affiliation: ChemPartner Co., Shanghai, China.
authors.forename: Haisong
authors.initials: H
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Lixia
authors.initials: L
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Huang
authors.affiliation: Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Minjun
authors.initials: M
authors.lastname: Yang
authors.affiliation: Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Kang
authors.affiliation: Shanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Shuting
authors.initials: S
authors.lastname: Chen
authors.affiliation: ChemPartner Co., Shanghai, China.
authors.forename: Alicia
authors.initials: A
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Shen
authors.affiliation: National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Arend
authors.initials: A
authors.lastname: von Stackelberg
authors.affiliation: 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.
authors.forename: Longjun
authors.initials: L
authors.lastname: Gu
authors.affiliation: St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Ferrando
authors.affiliation: 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.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Shengyue
authors.initials: S
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Bin-Bing S
authors.initials: BB
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D025461:Feedback, Physiological / Q000187:drug effects*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D015448:Leukemia, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011687:Purines / Q000096:biosynthesis; D012008:Recurrence; D012268:Ribose-Phosphate Pyrophosphokinase / Q000737:chemistry / Q000235:genetics*; D013763:Tetrahydrofolates / Q000008:administration & dosage
chemical_list: D011687:Purines; D013763:Tetrahydrofolates; C045894:lometrexol; D015122:Mercaptopurine; C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase; C030985:purine