Association of allele-specific methylation of the ASNS gene with asparaginase sensitivity and prognosis in T-ALL.

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.

• Authors: Koshi Akahane, Shunsuke Kimura, Kunio Miyake, Atsushi Watanabe, Keiko Kagami, Kentaro Yoshimura, Tamao Shinohara, Daisuke Harama, Shin Kasai, Kumiko Goi, Tomoko Kawai, Kenichiro Hata, Nobutaka Kiyokawa, Katsuyoshi Koh, Toshihiko Imamura, Keizo Horibe, A Thomas Look, Masayoshi Minegishi, Kanji Sugita, Junko Takita, Takeshi Inukai
• Journal: Blood advances (Blood Adv) Vol. 6 Issue 1 Pg. 212-224 (01 11 2022) ISSN: 2473-9537 [Electronic] United States
• PMID: 34535013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 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.

Chemical References

• Asparagine
• Asparaginase
• Aspartate-Ammonia Ligase
• Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
• ASNS protein, human

Topics

• Alleles
• Asparaginase (therapeutic use)
• Asparagine (genetics, metabolism)
• Aspartate-Ammonia Ligase (genetics, metabolism)
• Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor (genetics, metabolism)
• Cell Line, Tumor
• Child
• DNA Methylation
• Humans
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Prognosis