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Utility of ASNS gene methylation evaluated with the HPLC method as a pharmacogenomic biomarker to predict asparaginase sensitivity in BCP-ALL.
- Source :
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Epigenetics [Epigenetics] 2023 Dec; Vol. 18 (1), pp. 2268814. Date of Electronic Publication: 2023 Oct 15. - Publication Year :
- 2023
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Abstract
- Asparaginase is an important agent for the treatment of acute lymphoblastic leukaemia (ALL), but it is occasionally associated with severe adverse events. Thus, for safer and more efficacious therapy, a clinical biomarker predicting asparaginase sensitivity is highly anticipated. Asparaginase depletes serum asparagine by deaminating asparagine into aspartic acid, and ALL cells are thought to be sensitive to asparaginase due to reduced asparagine synthetase (ASNS) activity. We have recently shown that allele-specific methylation of the ASNS gene is highly involved in asparaginase sensitivity in B-precursor ALL (BCP-ALL) by using next-generation sequence (NGS) analysis of bisulphite PCR products of the genomic DNA. Here, we sought to confirm the utility of methylation status of the ASNS gene evaluated with high-performance liquid chromatography (HPLC) analysis of bisulphite PCR products for future clinical applications. In the global methylation status of 23 CpG sites at the boundary region of promoter and exon 1 of the ASNS gene, a strong positive correlation was confirmed between the mean percent methylation evaluated with the HPLC method and that with the NGS method in 79 BCP-ALL cell lines (R <superscript>2</superscript> = 0.85, p = 1.3 × 10 <superscript>-33</superscript> ) and in 63 BCP-ALL clinical samples (R <superscript>2</superscript> = 0.84, p = 5.0 × 10 <superscript>-26</superscript> ). Moreover, methylation status of the ASNS gene evaluated with the HPLC method was significantly associated with in vitro asparaginase sensitivities as well as gene and protein expression levels of ASNS. These observations indicated that the ASNS gene methylation status evaluated with the HPLC method is a reliable biomarker for predicting the asparaginase sensitivity of BCP-ALL.
- Subjects :
- Humans
Asparaginase genetics
Asparaginase metabolism
Asparaginase therapeutic use
Asparagine genetics
Asparagine metabolism
Asparagine therapeutic use
Chromatography, High Pressure Liquid
Pharmacogenetics
DNA Methylation
Cell Line, Tumor
Aspartate-Ammonia Ligase genetics
Aspartate-Ammonia Ligase metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1559-2308
- Volume :
- 18
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Epigenetics
- Publication Type :
- Academic Journal
- Accession number :
- 37839090
- Full Text :
- https://doi.org/10.1080/15592294.2023.2268814