AbstractBecause de novo purine synthesis (DNPS) is a target of widely used antileukemic agents (eg, methotrexate, mercaptopurine), we determined the rate of DNPS and the expression of genes involved in purine metabolism in different subtypes of acute lymphoblastic leukemia (ALL). Among 113 children with newly diagnosed ALL, lymphoblasts with the TEL-AML1 translocation had significantly lower DNPS than all other genetic subtypes of B-lineage ALL or T-lineage ALL (352 ± 57 versus 1001 ± 31 or versus 1315 ± 76 fmol/nmol/h, P < .0001). By assessing the expression of 82 genes involved in purine metabolism (KEGG pathway database) in ALL blasts from 38 patients with B-lineage ALL (14 with TEL-AML1, 24 without), we identified 16 genes that were differentially expressed in TEL-AML1–positive and TEL-AML1–negative ALL (P < .001, false discovery rate [FDR] = 5%). The pattern of expression of these 16 genes discriminated TEL-AML1–positive ALL with a true accuracy of 84% in an independent test set (n = 17, confidence interval 70% to 94%, P < .001). Western blots of selected genes documented corresponding levels of the proteins encoded. Differentially expressed genes included HPRT, IMPDH, PAICS, and GART, all of which were expressed at a significantly lower level in TEL-AML1 ALL. These findings have established that TEL-AML1 ALL has significantly lower de novo purine synthesis and differential expression of genes involved in purine metabolism.