Genetic background of acute lymphoblastic leukemia in children

• Project/Area Number: 19H03614
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Takagi Masatoshi 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (10406267)
• Co-Investigator(Kenkyū-buntansha): 盛武 浩 宮崎大学, 医学部, 教授 (40336300) ; 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) ; 重水 大智 国立研究開発法人国立長寿医療研究センター, メディカルゲノムセンター, 部長 (70617464)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 白血病 / 小児 / 遺伝的背景 / B細胞分化 / 急性リンパ性白血病 / レアバリアント / 疾患感受性 / 小児急性リンパ性白血病 / 乳児白血病 / 原発性免疫不全症

Outline of Research at the Start

小児ALL発症の遺伝的背景の全貌はまだ十分に解明されていない。これまで小児ALL患者582例のゲノムワイド関連解析から幾つかの疾患感受性ローカスを同定し、またＢ細胞分化にかかわる転写因子に注目し、レアバリアントを同定した。さらに、乳児ALL52例から、新規疾患感受性遺伝子候補を同定した。本研究では、これらの同定された候補遺伝子の機能解析やゲノム疫学解析により小児ALL発症にかかわる新規疾患感受性遺伝子を同定し、小児ALL発症に関する遺伝的背景の実態を明らかにする。

Outline of Final Research Achievements

To explore the genetic background of childhood acute lymphocytic leukemia (ALL), we analyzed genes involved in B-cell differentiation and identified 6 PAX5 and 8 TCF3 rare variants.
One patient with a variant of PAX5 was common variable immunodeficiency. Knock-in mice with this variant showed abnormal B cell differentiation and susceptibility to leukemogenesis.TCF3 variants retained normal transcriptional function. Therefore, in collaboration with a U.S. group, we analyzed 4,405 ALL samples and identified 106 variants, 8 of which were nonsense mutations.
We identified the PAX5 rare variant in familial cases of ALL. We identified additional 2 families and their clinical features, immune abnormalities, and genetics were characterized.

Academic Significance and Societal Importance of the Research Achievements

小児急性リンパ性白血病(ALL)の遺伝的な背景を明らかにすることにより、小児ALLの発症に関わる病態解明につながることが予測される。今回の研究により小児ALLの一部はB細胞分化にかかわる転写因子の異常を背景としていることが明らかになり、将来的にはこういった分子を標的とした治療法開発につなげていく必要があると考える。また小児ALLの一部が遺伝的な背景のもとに発症しているということは遺伝カウンセリングの適切な介入が必要なことを意味し、将来的な患者ケアに役立つ情報となると考える。

Research Products

• [Int'l Joint Research] INGEMM La Paz University Hospital(スペイン)
• [Int'l Joint Research] Technical University of Munich(ドイツ)
• [Int'l Joint Research] St. Jude Children's Reserch Hospital(米国)
• [Journal Article] Clinical Courses of IKAROS and CTLA4 Deficiencies: A Systematic Literature Review and Retrospective Longitudinal Study (2022)
  • Author(s): Hoshino A, Toyofuku E, Mitsuiki N, Yamashita M, Okamoto K, Yamamoto M, Kanda K, Yamato G, Keino D, Yoshimoto-Suzuki Y, Kamizono J, Onoe Y, Ichimura T, Nagao M, Yoshimura M, Tsugawa K, Igarashi T, Mitsui-Sekinaka K, Sekinaka Y, Doi T, Yasumi T, Nakazawa Y, Takagi M, Imai K, Nonoyama S, Morio T, Latour S, Kanegane H.
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 784901-784901
  • DOI: 10.3389/fimmu.2021.784901
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS (2021)
  • Author(s): Yamashita Motoi、Kuehn Hye Sun、Okuyama Kazuki、Okada Satoshi、Inoue Yuzaburo、Takagi Masatoshi、Kanegane Hirokazu、Takeuchi Masahiro、Shimojo Naoki、Tsumura Miyuki、Padhi Aditya K.、Zhang Kam Y. J.、Boisson Bertrand、Casanova Jean-Laurent、Ohara Osamu、Rosenzweig Sergio D.、Taniuchi Ichiro、Morio Tomohiro
  • Journal Title: Nature Immunology Volume: 22 Issue: 7 Pages: 893-903
  • DOI: 10.1038/s41590-021-00951-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomics analysis of leukaemia predisposition in X‐linked agammaglobulinaemia (2021)
  • Author(s): Nishimura, A. Naruto, T. Miyamoto, S. Grigg, A. Bosco, J. J. Hoshino, A. Amano, K. Iwamoto, S. Hirayama, M. Migita, M. Ohara, O. Takagi, M. Morio, T. van Zelm, M. C. Kanegane, H.
  • Journal Title: British Journal of Haematology Volume: 193 Issue: 6 Pages: 1277-1281
  • DOI: 10.1111/bjh.17459
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characteristics of Li‐Fraumeni Syndrome in Japan; A Review Study by the Special Committee of JSHT (2021)
  • Author(s): Funato M.、Tsunematsu Y.、Yamazaki F.、Tamura C.、Kumamoto T.、Takagi M.、Kato S.、Sugimura H.、Tamura K.
  • Journal Title: Cancer Science Volume: - Issue: 7 Pages: 2821-2834
  • DOI: 10.1111/cas.14919
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <i>NUDT15</i> variants confer high incidence of second malignancies in children with acute lymphoblastic leukemia (2021)
  • Author(s): Yoshida Masanori,Nakabayashi Kazuhiko,Yang Wentao,Sato-Otsubo Aiko,Tsujimoto Shin-ichi, Motohiro Kato et al
  • Journal Title: Blood Advances Volume: 5 Issue: 23 Pages: 5420-5428
  • DOI: 10.1182/bloodadvances.2021005507
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional characterization of a germline ETV6 variant associated with inherited thrombocytopenia, acute lymphoblastic leukemia, and salivary gland carcinoma in childhood (2020)
  • Author(s): Yoshino Hiroshi、Nishiyama Yohei、Kamma Hiroshi、Chiba Tomohiro、Fujiwara Masachika、Karaho Takehiro、Kogashiwa Yasunao、Morio Tomohiro、Yan Kunimasa、Bessho Fumio、Takagi Masatoshi
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 2 Pages: 217-222
  • DOI: 10.1007/s12185-020-02885-y
  • Peer Reviewed
• [Journal Article] Prevalence of germline GATA2 and SAMD9/9L variants in paediatric haematological disorders with monosomy 7 (2020)
  • Author(s): Yoshida, M. Tanase-Nakao, K. Shima, H. Shirai, R. Yoshida, K. Osumi, T. Deguchi, T. Mori, M. Arakawa, Y. Takagi, M. Miyamura, T. Sakaguchi, K. Toyoda, H. Ishida, H. Sakata, N. Imamura, T. Kawahara, Y. Morimoto, A. Koike, T. Yagasaki, H. Ito, S. Tomizawa, D. Kiyokawa, N. Narumi, S. Kato, M.
  • Journal Title: British Journal of Haematology Volume: 191 Issue: 5 Pages: 835-843
  • DOI: 10.1111/bjh.17006
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 生殖細胞系列PAX5バリアントをもつCVID を合併したBCP-ALLの病態解析 (2022)
  • Author(s): 宮本智史
  • Organizer: 第157回 小児血液腫瘍免疫懇話会
• [Presentation] Characteristics of Li-Fraumeni Syndrome in Japan; A Review Study by the Special Committee of the JSHT (2021)
  • Author(s): Funato M Tsunematsu Y Yamazaki F Tamura C Kumamoto T Takagi M Kato S Sugimura H Tamura K
  • Organizer: 第80回 日本癌学会学術総会
• [Presentation] Pediatric acute lymphoblastic leukemia predisposition caused by germline variants in the PAX5 gene (2021)
  • Author(s): Masatoshi Takagi
  • Organizer: Final meeting EU-COST Action LEGEND
  • Int'l Joint Research
• [Presentation] Pediatric acute lymphoblastic leukemia predisposition caused by germline variants in the PAX5 gene (2021)
  • Author(s): Adela Escudero Lopez
  • Organizer: 第156回 小児血液腫瘍免疫懇話会
• [Presentation] X連鎖無ガンマグロブリン血症における白血病発症因子のゲノム解析 (2020)
  • Author(s): 西村聡,成戸卓也,星野顕宏,天野敬史郎,岩本彰太郎,平山雅治,Andrew Grigg,Julian J.Bosco,右田昌宏,高木正稔,小原収,森尾友宏,Menno C.van Zelm,金兼弘和
  • Organizer: 第3回日本免疫不全・自己炎症学会総会・学術集会
• [Presentation] 生殖細胞系列遺伝子異常により発症する血液腫瘍 (2020)
  • Author(s): 髙木正稔
  • Organizer: 第24回栃木県血液疾患講演会
  • Invited
• [Presentation] 小児期にホジキンリンパ種を発症し、成人後に免疫グロブリン低下を指摘されALPS-FASと診断された一例 (2020)
  • Author(s): Yohei Nishiyama, Etsushi Toyofuku, Tsubasa Okano, Motoi Yamashita, Takahiro Kamiya, Akifumi Endo, Hirokazu Kanegane, Masatoshi Takagi, Kohsuke Imai, Tomohiro Morio
  • Organizer: 第62回日本小児血液・がん学会学術集会
• [Presentation] NUDT15 Variants Confer High Incidence of Secondary Malignancies of ALL in Children (2019)
  • Author(s): Yoshida, M. Nakabayashi, K. Sato-Otsubo, A. Tsujimoto, S. Yoshida, K. Shirai, R. Osumi, T. Yuza, Y. Takagi, M. Takahashi, H. Koh,K. Kinoshita, A. Hino, M. Imamura, T. Nakazawa, Y. Okuya, M. Kakuda, H. Sanada, M. Matsumoto, K. Tomizawa, D. Kiyokawa, N. Ohara, A. Manabe, A. Hata, K. Yang, J, J. Kato, M.
  • Organizer: 61st American Society of Hematology (ASH) Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Association of Germline Variants of TCF3 and PAX5 with Pediatric Acute Lymphoblastic Leukemia Development (2019)
  • Author(s): Miyamoto,S. Naruto,T. Morio, T. Urayama,KY Manabe, A. Takagi,M.
  • Organizer: 61st American Society of Hematology (ASH) Annual Meeting and Exposition
  • Int'l Joint Research
• [Presentation] Genomics Analysis of Leukemia Predisposition in X-Linked Agammaglobulinemia (2019)
  • Author(s): Nishimura A, Naruto T, Hoshino A, Amano K, Iwamoto S, Hirayama M, Grigg A, Bosco J J, Migita M, Takagi M, Ohara O, Morio T, van Zelm MC, Kanegane H
  • Organizer: 19th Biennial Meeting of the European Society of Immunodeficiencies (ESID2019)
  • Int'l Joint Research
• [Presentation] 小児のモノソミー7を伴う血液疾患における生殖細胞系列のSAMD9/9Lバリアント保有率 (2019)
  • Author(s): 吉田仁典, 中尾佳奈子, 島彦仁, 白井了太, 吉田馨, 辻本信一, 大隅朋生, 出口隆生4, 森麻希子5, 荒川ゆうき, 高木正稔, 宮村能子, 坂口公祥, 豊田秀実, 石田悠志, 坂田尚己, 今村俊彦, 川原勇太, 小池隆志, 富澤大輔, 清河信敬, 鳴海覚志, 加藤元博
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 遺伝性素因と白血病 (2019)
  • Author(s): 高木正稔
  • Organizer: 第12回研修医(初期・後期)のための血液学セミナー
  • Invited