Comprehensive gene analysis of clonal hematopoiesis in childhood aplastic anemia

2018 Fiscal Year Annual Research Report

• Project/Area Number: 17K16248
• Research Institution: Nagoya University
• Principal Investigator: 成田 敦 名古屋大学, 医学部附属病院, 助教 (20625149)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 再生不良性貧血 / 発作性夜間血色素尿症 / クローン性造血 / 骨髄異形成症候群 / 急性骨髄性白血病

Outline of Annual Research Achievements

HLA一致ドナーが得られない小児再生不良性貧血（AA）に対する標準治療は抗胸腺細胞グロブリンとシクロスポリンによる免疫抑制療法（Immunosuppressive therapy; IST）である。骨髄移植が実施できなかった症例においてもISTにより90%以上の長期生存が期待されるが、数年の経過中に約15%の症例ではクローン性造血が生じるとされる。
クローン性造血には夜間発作性血色素尿症（Paroxysmal nocturnal hemoglobinuria; PNH）を代表とする血液良性疾患の他に、骨髄異形成症候群（Myelodysplastic syndrome; MDS）および急性骨髄性白血病（Acute myeloid leukemia; AML）などの血液悪性疾患が含まれる。我々は小児AAの57症例を後方視的に解析した。観察期間中に5例がPNHを発症し、10年累積発症率は10.2% (95% CI, 3.6%-20.7%)であった。また、AAからPNHを発症した5例についてAA診断時とPNH発症時の検体をターゲットシーケンス解析した結果、AA診断時にはPIGA遺伝子変異を認めなかったが、PNH発症後にPIGA遺伝子変異を全例で検出した。
AAの経過中に7番染色体モノソミーを来した2例について、AA、MDS、AML発症時の検体を用いて全エクソーム解析を実施した。その結果、経過中にそれぞれ5つの付加遺伝子変異を検出し、このうちSETBP1変異を両者に認めた。
小児AA患者41症例について全エクソーム解析を実施した。複数例に同定された変異遺伝子の中に新規遺伝子X（2例）を認めた。追加検討で小児AA140症例のうち8症（6%）に遺伝子X変異を同定した。遺伝子Ｘの変異部位は同一であることから、機能獲得型変異であると考えられた。

Research Products

• [Journal Article] Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy (2019)
  • Author(s): Kato Koji、Maemura Ryo、Wakamatsu Manabu、Yamamori Ayako、Hamada Motoharu、Kataoka Shinsuke、Narita Atsushi、Miwata Shunsuke、Sekiya Yuko、Kawashima Nozomu、Suzuki Kyogo、Narita Kotaro、Doisaki Sayoko、Muramatsu Hideki、Sakaguchi Hirotoshi、Matsumoto Kimikazu、Kaga Makiko、Shimozawa Nobuyuki、Yoshida Nao、et al
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 18 Pages: 1～6
  • DOI: 10.1016/j.ymgmr.2018.11.001
  • Peer Reviewed / Open Access
• [Journal Article] Integration Mapping of piggyBac-Mediated CD19 Chimeric Antigen Receptor T Cells Analyzed by Novel Tagmentation-Assisted PCR (2018)
  • Author(s): Hamada Motoharu、Nishio Nobuhiro、Okuno Yusuke、Suzuki Satoshi、Kawashima Nozomu、Muramatsu Hideki、Tsubota Shoma、Wilson Matthew H、Morita Daisuke、Kataoka Shinsuke、Ichikawa Daisuke、Murakami Norihiro、Taniguchi Rieko、Suzuki Kyogo、Kojima Daiei、Narita Atsushi、Kojima Seiji、Nakazawa Yozo、Takahashi Yoshiyuki、et al
  • Journal Title: EBioMedicine Volume: 34 Pages: 18～26
  • DOI: 10.1016/j.ebiom.2018.07.008
  • Peer Reviewed / Open Access
• [Journal Article] Whole-exome analysis to detect congenital hemolytic anemia mimicking congenital dyserythropoietic anemia (2018)
  • Author(s): Hamada Motoharu、Doisaki Sayoko、Okuno Yusuke、Muramatsu Hideki、Hama Asahito、Kawashima Nozomu、Narita Atsushi、Nishio Nobuhiro、Yoshida Kenichi、Kanno Hitoshi、Manabe Atsushi、Taga Takashi、Takahashi Yoshiyuki、Miyano Satoru、Ogawa Seishi、Kojima Seiji
  • Journal Title: International Journal of Hematology Volume: 108 Pages: 306～311
  • DOI: 10.1007/s12185-018-2482-7
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic performance of 18F-FDG PET/CT and whole-body diffusion-weighted imaging with background body suppression (DWIBS) in detection of lymph node and bone metastases from pediatric neuroblastoma (2018)
  • Author(s): Ishiguchi Hiroaki、Ito Shinji、Kato Katsuhiko、Sakurai Yusuke、Kawai Hisashi、Fujita Naotoshi、Abe Shinji、Narita Atsushi、Nishio Nobuhiro、Muramatsu Hideki、Takahashi Yoshiyuki、Naganawa Shinji
  • Journal Title: Annals of Nuclear Medicine Volume: 32 Pages: 348～362
  • DOI: 10.1007/s12149-018-1254-z
  • Peer Reviewed / Open Access
• [Journal Article] Integrated molecular profiling of juvenile myelomonocytic leukemia (2018)
  • Author(s): Murakami Norihiro、Okuno Yusuke、Yoshida Kenichi、Shiraishi Yuichi、Nagae Genta、Suzuki Kyogo、Narita Atsushi、Sakaguchi Hirotoshi、Kawashima Nozomu、Wang Xinan、Xu Yinyan、Chiba Kenichi、Tanaka Hiroko、Hama Asahito、Sanada Masashi、Ito Masafumi、Kojima Seiji、Ogawa Seishi、Takahashi Yoshiyuki、Muramatsu Hideki、et al
  • Journal Title: Blood Volume: 131 Pages: 1576～1586
  • DOI: 10.1182/blood-2017-07-798157
  • Peer Reviewed / Open Access
• [Journal Article] Danaparoid reduces transplant-related mortality in stem cell transplantation for children (2018)
  • Author(s): Kato Koji、Sakaguchi Hirotoshi、Muramatsu Hideki、Sekiya Yuko、Kawashima Nozomu、Narita Atsushi、Doisaki Sayoko、Watanabe Nobuhiro、Yoshida Nao、Matsumoto Kimikazu
  • Journal Title: Pediatric Transplantation Volume: 22 Pages: e13099～e13099
  • DOI: 10.1111/petr.13099
  • Peer Reviewed / Open Access
• [Presentation] Relationship between plasma rabbit anti-thymocyte globulin level and response to immunosuppressive therapy in patients with severe aplastic anemia: Results of a multicenter, prospective, randomized study (2019)
  • Author(s): Atsushi Narita, Hideki Muramatsu, Yinyan Xu, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Nobuhiro Nishio, Asahito Hama, Hirohito Yamazaki, Shinji Nakao, Seiji Kojima, and Yoshiyuki Takahashi
  • Organizer: 45th Annual Meeting of the European Society for Blood and Marrow Transplantation
  • Int'l Joint Research
• [Presentation] Evalution of complication in cord blood transplantation from KIR ligand incompatible donor. (2019)
  • Author(s): Atsushi Narita, Shunsuke Miwata, Kotaro Narita, Hironobu Kitazawa, Shinsuke Kataoaka, Motoharu Hamada, Rieko Taniguchi, Daisuke Ichikawa, Norihiro Murakami, Kyogo Suzuki, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Hideki Muramatsu, Nobuhiro Nishio, Seiji Kojima, Yoshinori Ito, Takahahsi Yoshiyuki.
  • Organizer: 第41回造血細胞移植学会総会
• [Presentation] Randomized Trial of Two Dosages of Rabbit Antithymocyte Globulin in Patients with Aplastic Anemia (2018)
  • Author(s): Atsushi Narita, Xiaofan Zhu, Hideki Muramatsu, Xiaojuan Chen, Ye Guo, Wenyu Yang, Jingliao Zhang, Fang Liu, Jun Ho Jang, Hoon Kook, Hawk Kim, Kensuke Usuki, Hirohito Yamazaki, Yoshiyuki Takahashi, Shinji Nakao, Jong Wook Lee, and Seiji Kojima
  • Organizer: 60th American Society of Hematology Annual Meeting & Exposition
  • Int'l Joint Research
• [Presentation] シーケンスによる先天性骨髄不全症の診断 (2018)
  • Author(s): Atsushi Narita, Hideki Muramatsu, Yusuke Okuno, et al
  • Organizer: 第60回日本小児血液・がん学会学術集会
• [Presentation] Immune reconstitution following rabbit ATG therapy in patients with severe aplastic anemia (2018)
  • Author(s): Atsushi Narita, Hideki Muramatsu, Yinyan Xu, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Nobuhiro Nishio, Asahito Hama, Hirohito Yamazaki, Shinji Nakao, Seiji Kojima, and Yoshiyuki Takahashi
  • Organizer: 第80回日本血液学会学術集会