Elucidation of gene polymorphisms related with adverse events in the treatment of childhood acute lymphoblastic leukemia

• Project/Area Number: 17K10129
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hokkaido University (2019); St. Luke's International University (2017-2018)
• Principal Investigator: Manabe Atsushi 北海道大学, 医学研究院, 教授 (20292849)
• Co-Investigator(Kenkyū-buntansha): 田中 庸一 北里大学, 薬学部, 講師 (40525341) ; 浦山 ケビン 聖路加国際大学, 専門職大学院公衆衛生学研究科(公衆衛生大学院), 教授 (60726850)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 小児 / 白血病 / 治療毒性 / 遺伝子多型 / 薬理ゲノム学 / ゲノム薬理学 / 小児腫瘍学

Outline of Final Research Achievements

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and long-term survival is expected in roughly 80% of patients. However, treatment-related toxicity is still a problem. We conducted a pharmacogenomic study in children with ALL. As a result, MTHFR gene polymorphism was related with clearance of methotrexate (MTX) in high-dose MTX treatment (n=79) among 5 genes (SLCO1B1, SLC19A1, ABCB1, ABCC2, ABCG2, and MTHFR). The most relevant gene polymorphism related with hematotoxicity of 6-mercaptopurine was NUDT15 (n=239), but not TPMT, which was strongly correlated in Caucasians. The result was validated using another cohort of patients (n=55). The difference in ethnicity should be considered to interpret the pharmacogenomic data.

Academic Significance and Societal Importance of the Research Achievements

急性リンパ性白血病（ALL）は最も頻度の高い小児がんである。ALLの治療成績の改善はめざましく、約80％に長期生存が期待できるが、化学療法に伴う治療毒性は大きな問題である。近年のゲノム薬理学の進歩により、治療毒性に関わる遺伝子変異が同定されてきたが、人種による差異が大きい。本研究の結果、MTHFR遺伝子多型とメソトレキサートのクリアランスとの間に相関がみられた。また６-メルカプトプリンの血液毒性では、白人で意味のあるTPMT多型は有意でなく、NUDT15多型は有意であった。薬剤による有害事象は人種差が大きいため、日本人を対象にした遺伝子多型の検討は重要である。

Research Products

• [Int'l Joint Research] St. Jude Children’s Research Hospital(米国)
• [Int'l Joint Research] St. Jude Children’s Research Hospital(米国)
• [Journal Article] Nationwide survey of pediatric hypodiploid acute lymphoblastic leukemia in Japan (2019)
  • Author(s): Ishimaru Sae、Okamoto Yasuhiro、Imai Chihaya、Sakaguchi Hirotoshi、Taki Tomohiko、Hasegawa Daisuke、Cho Yuko、Kakuda Harumi、Sano Hideki、Manabe Atsushi、Imamura Toshihiko、Kato Motohiro、Arakawa Yuki、Shimonodan Hidemi、Sato Atsushi、Suenobu Souichi、et al.
  • Journal Title: Pediatrics International Volume: 61 Issue: 11 Pages: 1103-1108
  • DOI: 10.1111/ped.14006
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and molecular characteristics of MEF2D fusion-positive B-cell precursor acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion. (2019)
  • Author(s): Ohki K, Kiyokawa N, Hayashi Y, Koh K, Manabe A, Ohara A; Tokyo Children’s Cancer Study Group (TCCSG) et al.
  • Journal Title: Haematologica. Volume: 104(1) Issue: 1 Pages: 128-137
  • DOI: 10.3324/haematol.2017.186320
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Treatment and biology of pediatric acute lymphoblastic leukemia (2018)
  • Author(s): Kato M, Manabe A.
  • Journal Title: Pediatrics International Volume: 60 Issue: 1 Pages: 4-12
  • DOI: 10.1111/ped.13457
  • Peer Reviewed
• [Journal Article] Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese (2018)
  • Author(s): Urayama Kevin Y.、Takagi Masatoshi、Kawaguchi Takahisa、Matsuo Keitaro、Tanaka Yoichi、Ayukawa Yoko、Arakawa Yuki、Hasegawa Daisuke、Yuza Yuki、Kaneko Takashi、Noguchi Yasushi、Taneyama Yuichi、Ota Setsuo、Inukai Takeshi、Yanagimachi Masakatsu、Keino Dai、Koike Kazutoshi、Toyama Daisuke、Inazawa Johji 他16名
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 789-789
  • DOI: 10.1038/s41598-017-19127-7
  • Peer Reviewed / Open Access
• [Journal Article] Preclinical evaluation ofNUDT15-guided thiopurine therapy and its effects on toxicity and anti-leukemic efficacy (2018)
  • Author(s): Nishii R、Moriyama T、Janke LJ、Yang W、Suiter C、Lin TN、Li L、Kihira K、Toyoda H、Hofmann U、Schwab M、Takagi M、Morio T、Manabe A、Kham S、Jiang N、Rabin KR.、Kato M、Koh K、Yeoh AE、Hori H、Yang JJ.
  • Journal Title: Blood Volume: 印刷中 Issue: 22 Pages: 2466-2474
  • DOI: 10.1182/blood-2017-11-815506
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms (2018)
  • Author(s): Tsujimoto S, Osumi T, Uchiyama M, Shirai R, Moriyama T, Nishii R, Yamada Y, Kudo K, Sekiguchi M, Arakawa Y, Yoshida M, Uchiyama T, Terui K, Ito S, Koh K, Takita J, Ito E, Tomizawa D, Manabe A, Kiyokawa N, Yang JJ, Kato M.
  • Journal Title: Leukemia Volume: 32 Issue: 12 Pages: 2710-2714
  • DOI: 10.1038/s41375-018-0190-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia (2018)
  • Author(s): Tanaka Y, Nakadate H, Kondoh K, Nakamura K, Koh K, Manabe A
  • Journal Title: The Pharmacogenomics Journal Volume: 18 Issue: 2 Pages: 275-280
  • DOI: 10.1038/tpj.2017.12
  • Peer Reviewed
• [Journal Article] Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in Pediatric lymphoid neoplasms (2018)
  • Author(s): Tsujimoto S, Osumi T, Uchiyama M, Shirai R, Moriyama T, Nishii R, Yamada Y, Kudo K, Sekiguchi M, Arakawa Y, Yoshida M, Uchiyama T, Terui K, Ito S, Koh K, Takita J, Ito E, Tomizawa D, Manabe A, Kiyokawa N, Yang JJ, Kato M
  • Journal Title: Leukemia Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia (2017)
  • Author(s): Moriyama Takaya、Nishii Rina、Lin Ting-Nien、Kihira Kentaro、Toyoda Hidemi、Jacob Nersting、Kato Motohiro、Koh Katsuyoshi、Inaba Hiroto、Manabe Atsushi、Schmiegelow Kjeld、Yang Jun J.、Hori Hiroki
  • Journal Title: Pharmacogenetics and Genomics Volume: 27 Issue: 6 Pages: 236-239
  • DOI: 10.1097/fpc.0000000000000282
  • Peer Reviewed / Int'l Joint Research
• [Presentation] NUDT15 genetic variation is the strongest predictive marker of tolerance to 6-mercaptopurine in Japanese childhood ALL patients: A genome-wide association study. (2019)
  • Author(s): Tanaka Y, Urayama K, Mori M, Hasegawa D, Noguchi Y, Yanagimachi M, Keino D, Ota S, Akabane K, Hangai M, Kawaguchi T, Takagi M, Koh K, Matsuda F, Manabe A.
  • Organizer: アメリカ血液学会（ASH）
  • Int'l Joint Research
• [Presentation] 1.小児ALLにおける高用量メトトレキサート療法時の薬物クリアランスへ影響を及ぼす因子の検討 (2018)
  • Author(s): 田中庸一、康 勝好、真部 淳
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 患者の年齢と肥満度の6-メルカプトプリン投与量への影響 (2018)
  • Author(s): 田中庸一、康 勝好、真部 淳
  • Organizer: 第60回日本小児血液・がん学会学術集会
• [Presentation] 3.Tolerable dose of 6-mercaptopurine and prognostic impact of NUDT15-deficient genotype in childhood acute lymphoblastic leukemia (2018)
  • Author(s): Tanaka Y, Kato M, Arakawa Y, Hasegawa D, Fujimura J, Keino D, Sato A, Ueda T, Taneyama Y, Takagi M, Yamamoto M, Matsuoka M, Hino M, Hori H, Koh K, Moriyama T, Yeoh A, Yang JJ, Manabe A.
  • Organizer: 60th ASH Annual Meeting & Exposition
  • Int'l Joint Research