ArticleNature medicine2015
Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.
Abstract read
In one paragraph
Article in Nature medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 papers, 2 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
105citing papers in PubMed, 2 pooled it
–field-weighted citation impact
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
105 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Association ofHaematologica · 2024Pooled it
- Pooled it
- Integrated analysis of relapsed B-cell precursor Acute Lymphoblastic Leukemia identifies subtype-specific cytokine and metabolic signatures.Scientific reports · 2019Trial
- Personalized Therapy with Mercaptopurine in Acute Lymphoblastic Leukemia: Current Advances and Challenges.Current treatment options in oncology · 2026Review
- The molecular basis of ADP-ribose pyrophosphorylation by a phage PRPS-like enzyme in NAD+ reconstitution.Nucleic acids research · 2026Article
- Dynamic control of nucleotide metabolism in physiology and disease.Nature cell biology · 2026Review
- Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.Nature metabolism · 2025Article
- The genomic landscape of relapsed infant and childhood KMT2A-rearranged acute leukemia.Nature communications · 2025Article
- Treatment-related mutagenic processes in acute lymphoblastic leukemia.Haematologica · 2025Review
- The NUDIX hydrolase NUDT5 influences purine nucleotide metabolism and thiopurine pharmacology.The Journal of clinical investigation · 2025Article
- PRPS2 enhances RNA mNature communications · 2025Article
- Utility of the Base Editing System for Introducing Drug-Resistant Gene Mutations Into Human Leukemia Cellular Models.Cureus · 2025Article
- Article
- SJPedPanel: A Pan-Cancer Gene Panel for Childhood Malignancies to Enhance Cancer Monitoring and Early Detection.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Histidine re-sensitizes pediatric acute lymphoblastic leukemia to 6-mercaptopurine through tetrahydrofolate consumption and SIRT5-mediated desuccinylation.Cell death & disease · 2024Article
- Metabolic Hallmarks for Purine Nucleotide Biosynthesis in Small Cell Lung Carcinoma.Molecular cancer research : MCR · 2024Article
- Hypoxanthine in the microenvironment can enable thiopurine resistance in acute lymphoblastic leukemia.Frontiers in oncology · 2024Article
- Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation.Nature chemical biology · 2024Article
- Review
- Chromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia.Nature communications · 2023Article
45 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
Authors and funding
31 authors.
Benshang Li1] 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.
Hui Li1] 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.
Yun BaiShanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
Renate Kirschner-Schwabe1] Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany. [2] German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.ORCID 0000000163353274
Jun J YangSt. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Yao Chen1] 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.
Gang LuShanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
Gannie TzonevaInstitute for Cancer Genetics, Columbia University, New York, New York, USA.
Xiaotu MaSt. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Tongmin Wu1] 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.
Wenjing LiNational Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
Haisong LuChemPartner Co., Shanghai, China.
Lixia Ding1] 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.
Huanhuan LiangKey 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.
Xiaohang HuangKey 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.
Minjun YangShanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
Lei JinShanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
Hui KangShanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
Shuting ChenShanghai Ministry of Science and Technology Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
Alicia DuChemPartner Co., Shanghai, China.
Shuhong Shen1] 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.
Jianping DingNational Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
Hongzhuan Chen1] 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.
Jing ChenKey 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.
Arend von StackelbergDepartment of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Longjun GuKey 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.
Jinghui ZhangSt. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Adolfo FerrandoInstitute for Cancer Genetics, Columbia University, New York, New York, USA.
Jingyan TangKey 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.
Shengyue Wang1] 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.
Bin-Bing S Zhou1] 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.
Funding
Viral Vector Technology (VVTSR)P30CA021765 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI CHARLES ROBERTS · 1985 to 2026
$166.9MHoward Hughes Medical InstituteNCI NIH HHS CA21765NCI NIH HHS P30 CA021765
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.
Indexed as
AdolescentChildChild, PreschoolExomeFeedback, PhysiologicalFemaleHigh-Throughput Nucleotide SequencingHumansInfantLeukemia, B-CellMaleMercaptopurineMutationPrecursor Cell Lymphoblastic Leukemia-LymphomaPurinesRecurrencelometrexolMercaptopurinePRPS1 protein, humanpurinePurinesRibose-Phosphate PyrophosphokinaseTetrahydrofolates
Identifiers
What OpenQuestion holds
Textmetadata
LicenceTDM
Read underepoch 390
Registered trials
None linked
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.