Comprehensive gene analysis of clonal hematopoiesis in childhood aplastic anemia

• Project/Area Number: 17K16248
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Nagoya University
• Principal Investigator: Atsushi Narita 名古屋大学, 医学部附属病院, 助教 (20625149)
• Research Collaborator: TAKAHASHI Yoshiyuki ; MURAMATSU Hideki ; OKUNO Yusuke ; NAKATOCHI Masahiro
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• 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 / 血液学 / 小児 / 夜間発作性血色素尿症

Outline of Final Research Achievements

We retrospectively studied 57 children with Aplastic anemia (AA) between 1992 and 2010. During the follow‐up, five patients developed clinical PNH, in whom somatic PIGA mutations were detected by targeted sequencing. The 10‐year probability of clinical PNH development was 10.2% (95% CI, 3.6%-20.7%). Furthermore, the detection of minor PNH clones by flow cytometry at AA diagnosis was a risk factor for the subsequent development of clinical PNH.
We performed whole-exome sequencing (WES) of paired bone marrow-germline reference samples in 41 patients. WES detected reccurent gene X mutations as a novel mutational target. Gene X mutation may be associated the pahophisiology of AA.

Academic Significance and Societal Importance of the Research Achievements

小児再生不良性貧血（AA）に発作性夜間血色素尿症（PNH）が合併することが知られている。我々は小児AA患者57例をの長期予後を調査したところ、観察期間中に5例がPNHを発症しており、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例では、AA診断時のフローサイトメトリーで微小PNH血球が全例で陽性であった。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。

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、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、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 Issue: 3 Pages: 306-311
  • DOI: 10.1007/s12185-018-2482-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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): Hiroaki Ishiguchi, Shinji Ito, Katsuhiko Kato, Yusuke Sakurai, Hisashi Kawai, Naotoshi Fujita, Shinji Abe, Atsushi Narita, Nobuhiro Nishio, Hideki Muramatsu, Yoshiyuki Takahashi, Shinji Naganawa
  • Journal Title: Ann Nucl Med. Volume: 32(5) Issue: 5 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 N, Okuno Y, Yoshida K, Shiraishi Y, Nagae G, Suzuki K, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Ito M, Hirayama M, Watanabe A, Ueno T, Kojima S, Aburatani H, Mano H, Miyano S, Ogawa S, Takahashi Y, Muramatsu H
  • Journal Title: Blood Volume: 131 Issue: 14 Pages: 1576-1586
  • DOI: 10.1182/blood-2017-07-798157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Danaparoid reduces transplant-related mortality in stem cell transplantation for children (2017)
  • 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 Issue: 2
  • DOI: 10.1111/petr.13099
  • Peer Reviewed / Open Access
• [Journal Article] Development of clinical paroxysmal nocturnal haemoglobinuria in children with aplastic anaemia (2017)
  • Author(s): Narita Atsushi、Muramatsu Hideki、Okuno Yusuke、Sekiya Yuko、Suzuki Kyogo、Hamada Motoharu、Kataoka Shinsuke、Ichikawa Daisuke、Taniguchi Rieko、Murakami Norihiro、Kojima Daiei、Nishikawa Eri、Kawashima Nozomu、Nishio Nobuhiro、Hama Asahito、Takahashi Yoshiyuki、Kojima Seiji
  • Journal Title: British Journal of Haematology Volume: 178 Issue: 6 Pages: 954-958
  • DOI: 10.1111/bjh.14790
  • 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
• [Presentation] Clinical sequencing of 375 patients with inherited and acquired bone marrow failure syndromes (2017)
  • Author(s): Hideki M, Okuno Y, Yoshida K, Shiraishi Y, Doisaki S, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Takahashi Y, Kanno H, Yamaguchi H, Ohga S, Manabe A, Harigae H, Kunishima S, Ishii E, Kobayashi M, Koike K, Watanabe K, Ito E, Takata M, Yabe M, Ogawa S, Miyano S, and Kojima S
  • Organizer: EWOG-S/SAA2017
  • Int'l Joint Research
• [Presentation] Genetic background of idiopathic bone marrow failure syndromes in children (2017)
  • Author(s): Narita A, Hideki M, Okuno Y, Yoshida K, Shiraishi Y, Chiba K, Tanaka H, Wang X, Kojima D, Xu Y, Kawashima N, Nishio N, Hama A, Takahashi Y, Hasegawa D, Manabe A, Sakaguchi H, Yoshida N, Kato K, Miyano S, Ito M, Ogawa S and Kojima S
  • Organizer: EWOG-S/SAA2017
  • Int'l Joint Research
• [Presentation] Clinical sequencing in inherited bone marrow failure syndromes (2017)
  • Author(s): Okuno Y
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Germline mutation in pediatric patients with aplastic anemia (2017)
  • Author(s): Narita A, Muramatsu H, Okuno Y, Wang X, Xu Y, Kawashima N, Nishio N, Hama A, Sakaguchi H, Yoshida N, Kato K, Kojima S and Takahashi Y
  • Organizer: 第59回日本小児血液・がん学会
• [Presentation] ターゲットシーケンス解析を施行した小児造血不全移植例の解析 (2017)
  • Author(s): Muramatsu H, Okuno Y, Yoshida K, Shiraishi Y, Doisaki S, Narita A and Kojima S, et al
  • Organizer: 第40回日本造血細胞移植学会総会