ArticleBlood2020
Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL.
Article in Blood, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- Impact of p53 Target Genes on Drug Resistance in TP53-Mutated B-Cell Precursor Acute Lymphoblastic Leukemia.Cancer medicine · 2026Article
- Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy.JCI insight · 2026Article
- A characteristic gene expression profile regulated by ACIN1::NUTM1 fusion in a newly identified infant leukaemic cell line and an ACIN1::NUTM1-inducible model.British journal of haematology · 2025Article
- Toward Safer Biotherapeutics: Expression and Characterization of a Humanized Chimeric L-Asparaginase inInternational journal of molecular sciences · 2025Article
- Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling.The Journal of clinical investigation · 2025Article
- Targeting Asparagine Metabolism in Solid Tumors.Nutrients · 2025Review
- Molecular and cellular mechanisms of chemoresistance in paediatric pre-B cell acute lymphoblastic leukaemia.Cancer metastasis reviews · 2024Review
- Utility ofEpigenetics · 2023Article
- Identification and validation of novel biomarkers associated with immune infiltration for the diagnosis of osteosarcoma based on machine learning.Frontiers in genetics · 2023Article
- Amino acid stress response genes promote L-asparaginase resistance in pediatric acute lymphoblastic leukemia.Blood advances · 2022Article
- Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy.Cancers · 2022Review
- Association of allele-specific methylation of the ASNS gene with asparaginase sensitivity and prognosis in T-ALL.Blood advances · 2022Article
- Tamoxifen resistance-related ceRNA network for breast cancer.Frontiers in cell and developmental biology · 2022Article
- NUDT15 polymorphism and NT5C2 and PRPS1 mutations influence thiopurine sensitivity in acute lymphoblastic leukaemia cells.Journal of cellular and molecular medicine · 2021Article
- Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia.International journal of molecular sciences · 2021Review
- Assessment of MGMT methylation status using high-performance liquid chromatography in newly diagnosed glioblastoma.Clinical epigenetics · 2020Article
Corrections and comments
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Authors and funding
27 authors at 14 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 ASNS gene has a typical CpG island in its promoter. Thus, methylation of the ASNS CpG island could be one of the epigenetic mechanisms for ASNS gene silencing in BCP-ALL. To gain deep insights into the pharmacogenomics of asparaginase therapy, we investigated the association of ASNS methylation status with asparaginase sensitivity. The ASNS CpG island is largely unmethylated in normal hematopoietic cells, but it is allele-specifically methylated in BCP-ALL cells. The ASNS gene is located at 7q21, an evolutionally conserved imprinted gene cluster. ASNS methylation in childhood BCP-ALL is associated with an aberrant methylation of the imprinted gene cluster at 7q21. Aberrant methylation of mouse Asns and a syntenic imprinted gene cluster is also confirmed in leukemic spleen samples from ETV6-RUNX1 knockin mice. In 3 childhood BCP-ALL cohorts, ASNS is highly methylated in BCP-ALL patients with favorable karyotypes but is mostly unmethylated in BCP-ALL patients with poor prognostic karyotypes. Higher ASNS methylation is associated with higher L-asparaginase sensitivity in BCP-ALL through lower ASNS gene and protein expression levels. These observations demonstrate that silencing of the ASNS gene as a result of aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL.
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