GRCh38 · COSMIC v99

Summary

This section shows a summary for the selected study (COSU identifier) or publication (COSP identifier). Studies may have been performed by the Sanger Institute Cancer Genome Project, or imported from the ICGC/TCGA. You can see more information on the help pages.

Reference
Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.
Paper ID
COSP42047
Authors
Li B, Li H, Bai Y, Kirschner-Schwabe R, Yang JJ, Chen Y, Lu G, Tzoneva G, Ma X, Wu T, Li W, Lu H, Ding L, Liang H, Huang X, Yang M, Jin L, Kang H, Chen S, Du A, Shen S, Ding J, Chen H, Chen J, von Stackelberg A, Gu L, Zhang J, Ferrando A, Tang J, Wang S and Zhou BB
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.
Journal
Nature medicine, 2015;21(6):563-71
ISSN: 1546-170X
PMID: 25962120 (view at PubMed or Europe PMC)
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.
Paper Status
Curated