Lometrexol treatment of PRPS1 A190T- and S103T-expressing cells inhibited de novo purine synthesis and reversed PRPS1 mutant-driven thiopurine drug resistance (Fig. 4e,f and Supplementary Fig. 26). This striking result suggests that pharmacological inhibition of GART may serve as a therapeutic strategy to overcome PRPS1 mutation-driven thiopurine resistance in relapsed ALL.