Functional analysis of novel genes related to aplastic anemia using mouse models.

• Project/Area Number: 19K08297
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nagoya University
• Principal Investigator: Atsushi Narita 名古屋大学, 医学部附属病院, 助教 (20625149)
• Co-Investigator(Kenkyū-buntansha): 奥野 友介 名古屋市立大学, 医薬学総合研究院(医学), 教授 (00725533) ; 高橋 義行 名古屋大学, 医学系研究科, 教授 (40432273)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 再生不良性貧血 / 次世代シーケンサー / マウス / 骨髄増殖 / 免疫回避 / 網羅的遺伝子解析

Outline of Research at the Start

再生不良性貧血（Aplastic anemia; AA）は、造血幹細胞に対する自己免疫反応が原因で起こると考えられているが病態の解明は十分ではない。我々は、小児AA患者41症例の全エクソーム解析を通じて、血液疾患との関連性についてはこれまでに報告がない、新規遺伝子Xの体細胞変異を2例で同定した。さらに我々は、小児AA140症例についてPyro sequencing法を実施し、8症例（6%）で同様に遺伝子Xの変異を確認した。本研究の目的は、遺伝子Xの変異マウスモデルを用いて、AAにおける新規遺伝子Xの機能的意義を検討し、AAの病態機構を明らかにすることである。

Outline of Final Research Achievements

We recurrently identified novel gene X mutations using whole exome analysis in children with aplastic anemia. We hypothesized that mutations in gene X might confer an advantage in myeloproliferation or immune escape in aplastic anemia patients. Using a mutant mouse model of gene X, we examined the functional significance of the novel gene X mutant allele in aplastic anemia. Bone marrow specimens were collected from gene X mutant mice and subjected to colony assay, expression analysis by RNA sequencing, MHC deletion analysis, and bone marrow competitive transplantation experiments. In all results, however, mutations in gene X showed no advantage over controls in myeloproliferation or immune escape.

Academic Significance and Societal Importance of the Research Achievements

本研究では再生不良性貧血における新規遺伝子X変異アリルの機能的意義を検討した。遺伝子Xは、がん悪性化にも関与する遺伝子の制御因子として知られているが、血液疾患との関連性についてはこれまでに報告がない。本研究は、再生不良性貧血の病態機構に関する研究を補完するだけでなく、遺伝子Xにおける機能について解析を実施することで、他疾患の病態解明にも影響を与えうるものである。

Research Products

• [Journal Article] 綜説 血球テロメア長測定の臨床的意義 (2022)
  • Author(s): 成田 敦
  • Journal Title: 小児科 Volume: 63 Issue: 2 Pages: 199-206
  • DOI: 10.18888/sh.0000002074
  • ISSN: 0037-4121
  • Year and Date: 2022-02-01
• [Journal Article] Minor PNH clones do not distinguish inherited bone marrow failure syndromes from immune-mediated aplastic anemia (2022)
  • Author(s): Narita Atsushi、Miwata Shunsuke、Imaya Masayuki、Tsumura Yusuke、Yamamori Ayako、Wakamatsu Manabu、Hamada Motoharu、Taniguchi Rieko、Okuno Yusuke、Muramatsu Hideki、Takahashi Yoshiyuki
  • Journal Title: Blood Advances Volume: 6 Issue: 8 Pages: 2517-2519
  • DOI: 10.1182/bloodadvances.2021006044
  • Peer Reviewed
• [Journal Article] Prospective validation of the provisional entity of refractory cytopenia of childhood, proposed by the World Health Organization (2021)
  • Author(s): Hama Asahito、Hasegawa Daisuke、Manabe Atsushi、Nozawa Kazue、Narita Atsushi、Muramatsu Hideki、Kosaka Yoshiyuki、Kobayashi Masao、Koh Katsuyoshi、Takahashi Yoshiyuki、Watanabe Kenichiro、Ohara Akira、Ito Masafumi、Kojima Seiji
  • Journal Title: British Journal of Haematology Volume: 196 Issue: 4 Pages: 1031-1039
  • DOI: 10.1111/bjh.17921
  • Peer Reviewed
• [Journal Article] Simple and robust methylation test for risk stratification of patients with juvenile myelomonocytic leukemia (2021)
  • Author(s): Kitazawa Hironobu、Okuno Yusuke、Muramatsu Hideki、Aoki Kosuke、Murakami Norihiro、Wakamatsu Manabu、Suzuki Kyogo、Narita Kotaro、Kataoka Shinsuke、Ichikawa Daisuke、Hamada Motoharu、Taniguchi Rieko、Kawashima Nozomu、Nishikawa Eri、Narita Atsushi、et.al
  • Journal Title: Blood Advances Volume: 5 Issue: 24 Pages: 5507-5518
  • DOI: 10.1182/bloodadvances.2021005080
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrated diagnosis based on transcriptome analysis in suspected pediatric sarcomas (2021)
  • Author(s): Ichikawa Daisuke、Yamashita Kyoko、Okuno Yusuke、Muramatsu Hideki、Murakami Norihiro、Suzuki Kyogo、Kojima Daiei、Kataoka Shinsuke、Hamada Motoharu、Taniguchi Rieko、Nishikawa Eri、Kawashima Nozomu、Narita Atsushi、Nishio Nobuhiro、Hama Asahito、Kasai Kenji、Mizuno Seiji、Shimoyama Yoshie、Nakaguro Masato、et.al
  • Journal Title: npj Genomic Medicine Volume: 6 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41525-021-00210-y
  • Peer Reviewed / Open Access
• [Journal Article] Autoantibodies against the plakin family proteins as a novel marker for chronic graft-versus-host disease of the lung (2021)
  • Author(s): Kawashima Nozomu、Nishikawa Eri、Tsuchisaka Atsunari、Hashimoto Takashi、Okuno Yusuke、Hamada Motoharu、Ichikawa Daisuke、Narita Atsushi、Muramatsu Hideki、Nishio Nobuhiro、Kojima Seiji、Muro Yoshinao、Takahashi Yoshiyuki
  • Journal Title: Bone Marrow Transplantation Volume: 56 Issue: 9 Pages: 2291-2294
  • DOI: 10.1038/s41409-021-01335-5
  • Peer Reviewed
• [Journal Article] Echocardiography Monitoring of Pulmonary Hypertension after Pediatric Hematopoietic Stem Cell Transplantation: Pediatric Pulmonary Arterial Hypertension and Pulmonary Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation (2021)
  • Author(s): Kawashima Nozomu、Fukasawa Yoshie、Nishikawa Eri、Ohta-Ogo Keiko、Ishibashi-Ueda Hatsue、Hamada Motoharu、Ichikawa Daisuke、Narita Atsushi、Okuno Yusuke、Muramatsu Hideki、Nishio Nobuhiro、Kojima Seiji、Kato Taichi、Takahashi Yoshiyuki
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 9 Pages: 786.e1-786.e8
  • DOI: 10.1016/j.jtct.2021.05.017
  • Peer Reviewed
• [Journal Article] Relationship between plasma rabbit anti‐thymocyte globulin concentration and immunosuppressive therapy response in patients with severe aplastic anemia (2021)
  • Author(s): Narita Atsushi、Muramatsu Hideki、Ichikawa Daisuke、Hamada Motoharu、Nishikawa Eri、Suzuki Kyogo、Kawashima Nozomu、Okuno Yusuke、Nishio Nobuhiro、Hama Asahito、Yamazaki Hirohito、Nakao Shinji、Kojima Seiji、Takahashi Yoshiyuki
  • Journal Title: European Journal of Haematology Volume: 107 Issue: 2 Pages: 255-264
  • DOI: 10.1111/ejh.13644
  • Peer Reviewed
• [Journal Article] Clinical diagnostic value of telomere length measurement in inherited bone marrow failure syndromes (2021)
  • Author(s): Miwata Shunsuke、Narita Atsushi、Okuno Yusuke、Suzuki Kyogo、Hamada Motoharu、Yoshida Taro、Imaya Masayuki、Yamamori Ayako、Wakamatsu Manabu、Narita Kotaro、Kitazawa Hironobu、Ichikawa Daisuke、Taniguchi Rieko、Kawashima Nozomu、Nishikawa Eri、Nishio Nobuhiro、Kojima Seiji、Muramatsu Hideki、Takahashi Yoshiyuki
  • Journal Title: Haematologica Volume: 106 Issue: 9 Pages: 2511-2515
  • DOI: 10.3324/haematol.2021.278334
  • Peer Reviewed / Open Access
• [Journal Article] Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor (2021)
  • Author(s): Kataoka S, Kawashima N, Okuno Y, Muramatsu H, Miwata S, Narita K, Hamada M, Murakami N, Taniguchi R, Ichikawa D, Kitazawa H, Suzuki K, Nishikawa E, Narita A, Nishio N, Yamamoto H, Fukasawa Y, Kato T, Yamamoto H, Natsume J, Kojima S, Nishio I, Taketani T, Ohnishi H, Tahakashi Y.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 2 Pages: 639-644
  • DOI: 10.1016/j.jaci.2021.03.010
  • NAID: 120007192018
  • Peer Reviewed
• [Journal Article] 【小児で経験する「血液の異常」-血液疾患の鑑別とトピックス】各論:汎血球減少症 再生不良性貧血 (2021)
  • Author(s): 成田 敦
  • Journal Title: 小児内科 Volume: 53 Pages: 1137-1140
• [Journal Article] 特集 小児の貧血 10.再生不良性貧血の診断と治療 (2020)
  • Author(s): 成田 敦
  • Journal Title: 小児科 Volume: 61 Issue: 11 Pages: 1536-1544
  • DOI: 10.18888/sh.0000001513
  • ISSN: 0037-4121
  • Year and Date: 2020-10-01
• [Journal Article] Risk factors for secondary poor graft function after bone marrow transplantation in children with acquired aplastic anemia (2020)
  • Author(s): Hama A, Muramatsu H, Narita A, Nishikawa E, Kawashima N, Nishio N, Kojima S, Takahashi Y.
  • Journal Title: Pediatr Transplant. Volume: 24 Issue: 7
  • DOI: 10.1111/petr.13828
  • Peer Reviewed
• [Journal Article] 骨髄不全症と遺伝子異常 血球テロメア長測定の臨床的意義 (2020)
  • Author(s): 成田 敦
  • Journal Title: 臨床検査 Volume: 64 Pages: 761-765
• [Journal Article] Prospective randomized trial comparing two doses of rabbit anti-thymocyte globulin in patients with severe aplastic anaemia. (2019)
  • Author(s): Narita A, Zhu X, Muramatsu H, Chen X, Guo Y, Yang W, Zhang J, Liu F, Jang JH, Kook H, Kim H, Usuki K, Yamazaki H, Takahashi Y, Nakao S, Wook Lee J, Kojima S
  • Journal Title: Br J Haematol Volume: 187 Issue: 2 Pages: 227-237
  • DOI: 10.1111/bjh.16055
  • Peer Reviewed / Int'l Joint Research
• [Presentation] OUTCOME OF HAEMATOPOIETIC CELL TRANSPLANTATION IN CHILDREN WITH FANCONI ANAEMIA: A SINGLE- CENTERE EXPERIENCE (2021)
  • Author(s): Atsushi Narita, Yusuke Tsumura, Ryo Maemura, Masayuki Imaya, Ayako Ymamori, Taro Yoshida, Manabu Wakamatsu, Shunsuke Miwata, Koutaro Narita, Rieko Taniguchi, Motoharu Hamada, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Hideki Muramatsu, Nobuhiro Nishio, Seiji Kojima, and Yoshiyuki Takahashi
  • Organizer: 第43回日本造血細胞移植学会総会
• [Presentation] Clinical diagnostic value of telomere length measurement in inherited bone marrow failure syndromes (2021)
  • Author(s): Atsushi Narita, Shunsuke Miwata, Yusuke Okuno, Motoharu Hamada, Masayuki Imaya, Ayako Yamamori, Manabu Wakamatsu, Shinsuke Kataoka, Rieko Taniguchi, Nozomu Kawashima, Eri Nishikawa, Nobuhiro Nishio, Seiji Kojima, Hideki Muramatsu, Yoshiyuki Takahashi
  • Organizer: 9th International Symposium on MDS and SAA in childhood
  • Int'l Joint Research
• [Presentation] Blinatumomab in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (2021)
  • Author(s): Atsushi Narita, Daichi Sajiki, Yusuke Tsumura, Ryo Maemura, Masayuki Imaya, Ayako Yamamori, Manabu Wakamatsu, Rieko Tainguchi, Motoharu Hamada, Shinsuke Kataoka, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Hideki Muramatsu, Nobuhiro Nishio, and Yoshiyuki Takahashi
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Urinary biomarkers predicting treatment outcomes in neuroblastoma. (2021)
  • Author(s): Atsushi Narita, Akinari Hinoki, Kazuki Yokota, Motoharu Hamada, Shinsuke Kataoka, Nozomu Kawashima, Hideki Muramatsu, Nobuhiro Nishio, Hiroo Uchida, and Yoshiyuki Takahashi
  • Organizer: 第63回日本小児血液・がん学会
• [Presentation] Viral Reactivations in children with Aplastic Anemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation. (2020)
  • Author(s): Atsushi Narita, Yoshinori Ito, Nozomu Kawashima, Yusuke Okuno, Hideki Muramatsu, Nobuhiro Nishio, Yuka Torii, Juinichi Kawada, Seiji Kojima, and Yoshiyuki Takahashi
  • Organizer: 第62回日本小児血液・がん学会学術集会
• [Presentation] Reactivation of CMV/EBV is common in patients with severe aplastic anemia treated with rabbit ATG (2020)
  • Author(s): Atsushi Narita, Yoshinori Ito, Hideki Muramatsu, Motoharu Hamada, Daisuke Ichikawa, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Nobuhiro Nishio, Yuka Torii, Juinichi Kawada, Hirohito Yamazaki, Shinji Nakao, Seiji Kojima, and Yoshiyuki
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Allogeneic stem cell transplantation from alternative donors for children with aplastic anemia (2020)
  • Author(s): Atsushi Narita, Hideki Muramatsu, Masayuki Imaya, Ayako Ymamori, Taro Yoshida, Manabu Wakamatsu, Shunsuke Miwata, Koutaro Narita, Hironobu Kitazawa, Rieko Taniguchi, Motoharu Hamada, Daisuke Ichikawa, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Nobuhiro Nishio, Seiji Kojima, and Yoshiyuki Takahashi
  • Organizer: The 46th Annual Meeting of the European Group for Blood and Marrow Transplantation
  • Int'l Joint Research
• [Presentation] Allogeneic stem cell transplantation from alternative donors in children with aplastic anemia (2020)
  • Author(s): Atsushi Narita, Masayuki Imaya, Ayako Ymamori, Taro Yoshida, Manabu Wakamatsu, Shunsuke Miwata, Koutaro Narita, Hironobu Kitazawa, Rieko Taniguchi, Motoharu Hamada, Daisuke Ichikawa, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Hideki Muramatsu, Nobuhiro Nishio, Seiji Kojima, and Yoshiyuki Takahashi
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] High Natural killer Cell Count at Diagnosis Predicts a Good Response to Immunosuppressive Therapy in Aplastic Anemia (2019)
  • Author(s): Atsushi Narita, Hideki Muramatsu, Yinyan Xu, Motoharu Hamada, Daisuke Ichikawa, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Nobuhiro Nishio, Hirohito Yamazaki, Shinji Nakao, Seiji Kojima, and Yoshiyuki Takahashi
  • Organizer: 61th American Society of Hematology Annual Meeting & Exposition
  • Int'l Joint Research
• [Presentation] Correlation between plasma rabbit anti-thymocyte globulin level and response to immunosuppressive therapy in patients with severe aplastic anemia (2019)
  • Author(s): Atsushi Narita, Hideki Muramatsu, Motoharu Hamada, Daisuke Ichikawa, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Nobuhiro Nishio, Hirohito Yamazaki, Shinji Nakao, Seiji Kojima, and Yoshiyuki Takahashi
  • Organizer: 第61回日本小児血液・がん学会学術集会
• [Presentation] The high NK cell count at diagnosis predicts a good response to IST in aplastic anemia (2019)
  • Author(s): Atsushi Narita, Hideki Muramatsu, Yinyan Xu, Motoharu Hamada, Daisuke Ichikawa, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Nobuhiro Nishio, Hirohito Yamazaki, Shinji Nakao, Seiji Kojima, and Yoshiyuki Takahashi
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Haploidentical hematopoietic stem cell transplantation in children with aplastic anemia (2019)
  • Author(s): Atsushi Narita, Yoshiyuki Takahashi, Hideki Muramatsu, Maho Sato, Hiromasa Yabe, Yoshiko Hashii, Ken Tabuchi, Seiji Kojima, Nao Yoshida
  • Organizer: The 24th Congress of Asia-Pacific Blood and Marrow Transplantation Group
  • Int'l Joint Research