Thiopurine Resistance in Childhood ALL Is Mediated by PRPS1 Mutations

The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are prodrugs that are converted to cytotoxic purine antimetabolites and administered as part of combination chemotherapy in acute lymphoblastic leukemia (ALL). Thiopurine resistance contributes to ALL relapse, a leading cause of mortality in childhood cancers. To investigate how genetic mutations contribute to ALL relapse, Li, Li, Bai, and colleagues performed whole-exome sequencing of 16 matched samples obtained at diagnosis, remission, and relapse from children with ALL, and identified relapse-specific somatic mutations in phosphoribosyl pyrophosphate synthetase 1 (PRPS1), which encodes an enzyme essential for purine biosynthesis. PRPS1 mutations were confirmed in 24 (6.7%) of 358 relapsed B-cell ALL cases in validation cohorts and were associated with early disease relapse. Ultra-deep sequencing of serial bone marrow samples demonstrated that PRPS1 mutations were not present at diagnosis and increased exponentially before clinical relapse. Expression of gain-of-function PRPS1 mutants resulted in increased viability and resistance to apoptosis after treatment with 6-MP and 6-TG, confirming that PRPS1 confers thiopurine resistance. PRPS1 drug-resistant mutants exhibited reduced nucleotide feedback inhibition of PRPS1 activity, which allowed for continued activation of de novo purine biosynthesis despite elevated intracellular nucleotide concentrations. In addition, enhanced de novo purine biosynthesis resulted in increased levels of the metabolite hypoxanthine, which competitively inhibited 6-MP conversion. Importantly, knockdown of genes that encode for de novo pathway–specific enzymes or treatment with lometrexol, a small-molecule inhibitor of de novo purine biosynthesis that is in clinical development, reversed thiopurine drug resistance in PRPS1-mutant cells. Overall, these findings demonstrate that PRPS1 mutations can drive thiopurine resistance via defective negative feedback of nucleotide biosynthesis and competitive inhibition of prodrug activation and suggest that chemotherapeutic agents that inhibit de novo purine synthesis may effectively overcome thiopurine resistance in relapsed childhood ALL.

Li B, Li H, Bai Y, Kirschner-Schwabe R, Yang JJ, Chen Y, et al. Negative feedback–defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL. Nat Med 2015;21:563–71.

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