Involvement of methylation status of asparagine synthetase gene in asparaginase sensitivity of pediatric BCP-ALL

• Project/Area Number: 17K17774
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics; Medical pharmacy
• Research Institution: University of Yamanashi
• Principal Investigator: Watanabe Atsushi 山梨大学, 大学院総合研究部, 特任助教 (30610498)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 急性リンパ性白血病 / 個別化医療 / エピジェネティクス / ゲノム薬理学 / 薬剤感受性 / プレシジョン・メディシン / 急性白血病 / 遺伝子メチル化 / 小児がん / オーダーメイド医療

Outline of Final Research Achievements

Asparaginase, which depletes serum asparagine, is the important component in current chemotherapy for childhood BCP-ALL. Normal hematopoietic cells can produce asparagine by asparagine synthetase (ASNS) activity, while ALL cells are unable to synthesize adequate amounts of asparagine.
We investigated the association of ASNS methylation status with asparaginase sensitivity. ASNS CpG island is largely unmethylated in normal hematopoietic cells but is allele-specifically methylated in BCP-ALL cells. The ASNS gene is located at 7q21, an evolutionally conserved imprinted gene cluster. Clinically, in three childhood BCP-ALL cohorts, ASNS is highly methylated in BCP-ALL with favorable karyotypes but is mostly unmethylated in BCP-ALL with poor prognostic karyotypes.
These observations demonstrate that silencing of the ASNS gene due to aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL.

Academic Significance and Societal Importance of the Research Achievements

小児急性リンパ性白血病におけるASNS遺伝子プロモーター領域のメチル化状態がアスパラギナーゼの薬剤感受性に関連していることは、個別化医療の発展に貢献しうる。また、ALLの核型は従来より代表的な予後因子として知られていたが、そのゲノム薬理学的な根拠の一つが明らかになった。ASNS遺伝子のメチル化はアリル特異的に起こっていることが理解され、がんの薬剤感受性にゲノムインプリンティング現象が関連している新規の知見が得られた。これらの成果は、ALLに対する臨床応用にとどまらず、がんの分子細胞生物学を解明する礎となりうる。

Research Products

• [Presentation] Significance of methylation status and protein expression level of ASNS in asparaginase sensitivity of BCP-ALL (2020)
  • Author(s): Atsushi Watanabe, Kunio Miyake, Koushi Akahane, Tamao Shinohara, Shinpei Somazu, Kinuko Hirose, Hiroko Oshiro, Hiroki Sato, Kazuya Takahashi, Makoto Nakamura, Satoru Kojika, Kumiko Goi, Masako Abe, Keiko Kagami, Takeshi Inukai
  • Organizer: 日本血液学会