論文

査読有り 国際誌
2021年9月17日

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

Blood advances
  • 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
  • 全て表示

6
1
開始ページ
212
終了ページ
224
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1182/bloodadvances.2021004271

Asparaginase therapy is a key component of chemotherapy for T-cell acute lymphoblastic leukemia (T-ALL) patients. Asparaginase depletes serum asparagine by deamination into aspartic acid. Normal hematopoietic cells can survive due to asparagine synthetase (ASNS) activity, while leukemia cells are supposed to undergo apoptosis due to silencing of the ASNS gene. Since 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 PCR 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 childhood T-ALL patients 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 childhood 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 showed ASNS hypomethylation status. These observations demonstrate that ASNS hypomethylation status is associated with asparaginase resistance and is a poor prognostic biomarker in childhood T-ALL.

リンク情報
DOI
https://doi.org/10.1182/bloodadvances.2021004271
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/34535013
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753197
ID情報
  • DOI : 10.1182/bloodadvances.2021004271
  • PubMed ID : 34535013
  • PubMed Central 記事ID : PMC8753197

エクスポート
BibTeX RIS