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Association of allele-specific methylation of the ASNS gene with asparaginase sensitivity and prognosis in T-ALL.
- Source :
-
Blood advances [Blood Adv] 2022 Jan 11; Vol. 6 (1), pp. 212-224. - Publication Year :
- 2022
-
Abstract
- Asparaginase therapy is a key component of chemotherapy for patients with T-cell acute lymphoblastic leukemia (T-ALL). Asparaginase depletes serum asparagine by deamination into aspartic acid. Normal hematopoietic cells can survive due to asparagine synthetase (ASNS) activity, whereas leukemia cells are supposed to undergo apoptosis due to silencing of the ASNS gene. Because the ASNS gene has a typical CpG island in its promoter, its methylation status in T-ALL cells may be associated with asparaginase sensitivity. Thus, we investigated the significance of ASNS methylation status in asparaginase sensitivity of T-ALL cell lines and prognosis of childhood T-ALL. Sequencing of bisulfite polymerase chain reaction products using next-generation sequencing technology in 22 T-ALL cell lines revealed a stepwise allele-specific methylation of the ASNS gene, in association with an aberrant methylation of a 7q21 imprinted gene cluster. T-ALL cell lines with ASNS hypermethylation status showed significantly higher in vitro l-asparaginase sensitivity in association with insufficient asparaginase-induced upregulation of ASNS gene expression and lower basal ASNS protein expression. A comprehensive analysis of diagnostic samples from pediatric patients with T-ALL in Japanese cohorts (N = 77) revealed that methylation of the ASNS gene was associated with an aberrant methylation of the 7q21 imprinted gene cluster. In pediatric T-ALL patients in Japanese cohorts (n = 75), ASNS hypomethylation status was significantly associated with poor therapeutic outcome, and all cases with poor prognostic SPI1 fusion exclusively exhibited ASNS hypomethylation status. These observations show that ASNS hypomethylation status is associated with asparaginase resistance and is a poor prognostic biomarker in childhood T-ALL.<br /> (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Subjects :
- Alleles
Asparagine genetics
Asparagine metabolism
Cell Line, Tumor
Child
DNA Methylation
Humans
Prognosis
Asparaginase therapeutic use
Aspartate-Ammonia Ligase genetics
Aspartate-Ammonia Ligase metabolism
Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor genetics
Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor metabolism
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2473-9537
- Volume :
- 6
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Blood advances
- Publication Type :
- Academic Journal
- Accession number :
- 34535013
- Full Text :
- https://doi.org/10.1182/bloodadvances.2021004271