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Karyotype is an important prognostic factor in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but the underlying pharmacogenomics remain unknown. Asparaginase is an integral component in current chemotherapy for childhood BCP-ALL. Asparaginase therapy depletes serum asparagine. Normal hematopoietic cells can produce asparagine by asparagine synthetase (ASNS) activity, but ALL cells are unable to synthesize adequate amounts of asparagine. The ASNSgene has a typical CpG island in its promoter. Thus, methylation of the ASNSCpG island could be one of the epigenetic mechanisms for ASNSgene silencing in BCP-ALL. To gain deep insights into the pharmacogenomics of asparaginase therapy, we investigated the association of ASNSmethylation status with asparaginase sensitivity. The ASNSCpG island is largely unmethylated in normal hematopoietic cells, but it is allele-specifically methylated in BCP-ALL cells. The ASNSgene is located at 7q21, an evolutionally conserved imprinted gene cluster. ASNSmethylation in childhood BCP-ALL is associated with an aberrant methylation of the imprinted gene cluster at 7q21. Aberrant methylation of mouse Asnsand a syntenic imprinted gene cluster is also confirmed in leukemic spleen samples from ETV6-RUNX1knockin mice. In 3 childhood BCP-ALL cohorts, ASNSis highly methylated in BCP-ALL patients with favorable karyotypes but is mostly unmethylated in BCP-ALL patients with poor prognostic karyotypes. Higher ASNSmethylation is associated with higher L-asparaginase sensitivity in BCP-ALL through lower ASNSgene and protein expression levels. These observations demonstrate that silencing of the ASNSgene as a result of aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL.