Development of biomarkers to predict immunosuppressive therapy reactivity of aplastic anemia in children

• Project/Area Number: 15K09647
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nagoya University
• Principal Investigator: Muramatsu Hideki 名古屋大学, 医学部附属病院, 助教 (00572570)
• Co-Investigator(Kenkyū-buntansha): 奥野 友介 名古屋大学, 医学部附属病院, 特任講師 (00725533) ; 小島 勢二 名古屋大学, 医学系研究科, 名誉教授 (20313992)
• Co-Investigator(Renkei-kenkyūsha): OKUNO Yusuke 名古屋大学, 医学部附属病院, 特任講師 (00725533)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 小児血液学 / 再生不良性貧血 / 小児 / 免疫抑制療法 / トロンボポイエチン / 発作性夜間血色素尿症 / テロメア長

Outline of Final Research Achievements

We analyzed 113 patients with aplastic anemia (AA) in children and identified that absence of PNH-type blood cells and telomere shortening are independent poor prognostic factors for immunosuppressive therapy (IST) reaction (Haematologica 2015). We also identified that patients with high thrombopoietin (TPO) levels showed significantly lower response rate to IST (Pediatr Blood Cancer. 2016). Furthermore, we developed a target sequencing system of 184 genes associated with congenital hematopoietic failure (Genetics in Medicine 2017), and performed on 181 patients with idiopathic AA. In 26 cases, relevant gene mutations were identified, indicating the usefulness of screening for congenital hematopoietic failure genes in pediatric AA patients.

Research Products

• [Journal Article] Outcome of Hematopoietic Cell Transplantation for DNA-Double Strand Breakage Repair Disorders (2018)
  • Author(s): Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A,Imai K,Gennery AR
  • Journal Title: J Allergy Clin Immunol Volume: 141 Issue: 1 Pages: 322-328
  • DOI: 10.1016/j.jaci.2017.02.036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Journal Article] A case of GATA2-related myelodysplastic syndrome with unbalanced translocation der(1;7)(q10;p10). (2017)
  • Author(s): Kurata T, Shigemura T, Muramatsu H, Okuno Y, Nakazawa Y.
  • Journal Title: Pediatr Blood Cancer. Volume: 64(8) Issue: 8
  • DOI: 10.1002/pbc.26419
  • Peer Reviewed / Open Access
• [Journal Article] Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. (2017)
  • Author(s): Muramatsu H, 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, Kojima S.
  • Journal Title: Genet Med. Volume: - Issue: 7 Pages: 796-802
  • DOI: 10.1038/gim.2016.197
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Common Variable Immunodeficiency Caused by FANC Mutations (2017)
  • Author(s): Sekinaka Y., Mitsuiki N., Imai K., Yabe M., Yabe H., Mitsui-Sekinaka K., Honma K., Takagi M., Arai A., Yoshida K., Okuno Y., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Muramatsu H., Kojima S., Hira A., Takata M., Ohara O., Ogawa S., Morio T., Nonoyama S.
  • Journal Title: Journal of clinical immunology Volume: 37 Issue: 5 Pages: 434-444
  • DOI: 10.1007/s10875-017-0396-4
  • Peer Reviewed / Open Access
• [Journal Article] Long-term outcomes of 95 children with moderate aplastic anemia treated with horse antithymocyte globulin and cyclosporine. (2017)
  • Author(s): Nishikawa E, Yagasaki H, Hama A, Yabe H, Ohara A, Kosaka Y, Kudo K, Kobayashi R, Ohga S, Morimoto A, Watanabe KI, Yoshida N, Muramatsu H, Takahashi Y, Kojima S.
  • Journal Title: Pediatr Blood Cancer. Volume: 64(5) Issue: 5
  • DOI: 10.1002/pbc.26305
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic challenge of Diamond-Blackfan anemia in mothers and children by whole-exome sequencing (2017)
  • Author(s): Ichimura T, Yoshida K, Okuno Y, Yujiri T, Nagai K, Nishi M, Shiraishi Y, Ueno H, Toki T, Chiba K, Tanaka H, Muramatsu H, Hara T, Kanno H, Kojima S, Miyano S, Ito E, Ogawa S, Ohga S.
  • Journal Title: Int J Hematol. Volume: 105 Issue: 4 Pages: 515-520
  • DOI: 10.1007/s12185-016-2151-7
  • Peer Reviewed / Open Access
• [Journal Article] Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia. (2017)
  • Author(s): Ikeda F, Yoshida K, Toki T, Uechi T, Ishida S, Nakajima Y, Sasahara Y, Okuno Y, Kanezaki R, Terui K, Kamio T, Kobayashi A, Fujita T, Sato-Otsubo A, Shiraishi Y, Tanaka H, Chiba K, Muramatsu H, Kanno H, Ohga S, Ohara A, Kojima S, Kenmochi N, Miyano S, Ogawa S, Ito E.
  • Journal Title: Haematologica. Volume: - Issue: 3 Pages: e93-e96
  • DOI: 10.3324/haematol.2016.153932
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Cytokine-Based Diagnostic Program in Pediatric Aplastic Anemia and Hypocellular Refractory Cytopenia of Childhood. (2016)
  • Author(s): Elmahdi S, Hama A, Manabe A, Hasegawa D, Muramatsu H, Narita A, Nishio N, Ismael O, Kawashima N, Okuno Y, Xu Y, Wang X, Takahashi Y, Ito M, Kojima S.
  • Journal Title: Pediatr Blood Cancer Volume: 63 Issue: 4 Pages: 652-658
  • DOI: 10.1002/pbc.25799
  • Peer Reviewed
• [Journal Article] Markedly High Plasma Thrombopoietin (TPO) Level is a Predictor of Poor Response to Immunosuppressive Therapy in Children With Acquired Severe Aplastic Anemia. (2016)
  • Author(s): Elmahdi S, Muramatsu H, Narita A, Ismael O, Hama A, Nishio N, Okuno Y, Xu Y, Wang X, Takahashi Y, Kojima S.
  • Journal Title: Pediatr Blood Cancer Volume: 63 Issue: 4 Pages: 659-664
  • DOI: 10.1002/pbc.25820
  • Peer Reviewed
• [Journal Article] Immunosuppressive therapy for patients with Down syndrome and idiopathic aplastic anemia. (2016)
  • Author(s): Suzuki K, Muramatsu H, Okuno Y, Narita A, Hama A, Takahashi Y, Yoshida M, Horikoshi Y, Watanabe K, Kudo K, Kojima S.
  • Journal Title: Int J Hematol. Volume: 104 Issue: 1 Pages: 130-133
  • DOI: 10.1007/s12185-016-1997-z
  • Peer Reviewed
• [Journal Article] Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor. (2016)
  • Author(s): Elmahdi S, Muramatsu H, Narita A, Torii Y, Ismael O, Kawashima N, Okuno Y, Sekiya Y, Xu Y, Wang X, Hama A, Ito Y, Takahashi Y, Kojima S.
  • Journal Title: Pediatr Transplant. Volume: 20 Issue: 1 Pages: 105-113
  • DOI: 10.1111/petr.12620
  • Peer Reviewed / Open Access
• [Journal Article] Second allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia. (2015)
  • Author(s): Kudo K, Muramatsu H, Yoshida N, Kobayashi R, Yabe H, Tabuchi K, Kato K, Koh K, Takahashi Y, Hashii Y, Kawano Y, Inoue M, Cho Y, Sakamaki H, Kawa K, Kato K, Suzuki R, Kojima S.
  • Journal Title: Bone Marrow Transplant. Volume: 50 Issue: 10 Pages: 1312-1315
  • DOI: 10.1038/bmt.2015.153
  • Peer Reviewed / Open Access
• [Journal Article] GATA2 and secondary mutations in familial myelodysplastic syndromes and pediatric myeloid malignancies. (2015)
  • Author(s): Wang X, Muramatsu H, Okuno Y, Sakaguchi H, Yoshida K, Kawashima N, Xu Y, Shiraishi Y, Chiba K, Tanaka H, Saito S, Nakazawa Y, Masunari T, Hirose T, Elmahdi S, Narita A, Doisaki S, Ismael O, Makishima H, Hama A, Miyano S, Takahashi Y, Ogawa S, Kojima S.
  • Journal Title: Haematologica. Volume: 100 Issue: 10 Pages: 1304-15
  • DOI: 10.3324/haematol.2015.127092
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparison of long-term outcomes between children with aplastic anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine. (2015)
  • Author(s): Hama A, Takahashi Y, Muramatsu H, Ito M, Narita A, Kosaka Y, Tsuchida M, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Kojima S.
  • Journal Title: Haematologica. Volume: 100 Issue: 11 Pages: 1426-1433
  • DOI: 10.3324/haematol.2015.128553
  • Peer Reviewed / Open Access
• [Journal Article] Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia. (2015)
  • Author(s): Narita A, Muramatsu H, Sekiya Y, Okuno Y, Sakaguchi H, Nishio N, Yoshida N, Wang X, Xu Y, Kawashima N, Doisaki S, Hama A, Takahashi Y, Kudo K, Moritake H, Kobayashi M, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Kojima S; Japan Childhood Aplastic Anemia Study Group.
  • Journal Title: Haematologica. Volume: 100 Issue: 12 Pages: 1546-1552
  • DOI: 10.3324/haematol.2015.132530
  • Peer Reviewed / Open Access
• [Presentation] Bone marrow transplantation for children with acquired bone marrow failure (2017)
  • Author(s): Hama A, Manabe A, Hasegawa D, Nozawa K, Suzuki K, Narita A, Muramatsu H, Takahashi Y, Watanabe K, Ohara A, Ito M and Kojima S.
  • Organizer: EWOG-S/SAA2017
  • Int'l Joint Research
• [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] 次世代シークエンスによるファンコニ貧血遺伝子診断が可能な時代におけるFANCD2モノユビキチンの意義 (2017)
  • Author(s): 川島希, 奥野友介, 村松秀城, 濱麻人, 片岡伸介, 濱田太立, 市川大輔, 村上典寛, 小島大英, 鈴木喬悟, 西川英里, 成田敦, 西尾信博, 中沢洋三, 小島勢二, 高橋義行.
  • Organizer: 第79回日本血液学会学術集会
• [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] 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: 第79回日本血液学会学術集会
• [Presentation] Correlation of bone marrow morphology with clinical findings and gene alterations in patients with Diamond-Blackfan anemia (2017)
  • Author(s): Hama A, Tsutomu Toki, Akie Kobayashi, Muramatsu H, Okuno Y, Daisuke Hasegawa, Kazue Nozawa, Takahashi Y, Ken-ichiro Watanabe, Atsushi Manabe, Masafumi Ito, Etsuro Ito, and Kojima S.
  • Organizer: 第59回日本小児血液・がん学会
• [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] Risk Factors for Donor-Type Aplasia after Bone Marrow Transplant in Children with Acquired Bone Marrow Failure (2017)
  • Author(s): Hama A, Muramatsu H, Narita A, Kotaro Narita, Hironobu Kitazawa, Hamada M, Kataoka S, Murakami N, Ichikawa D, Taniguchi R, Kojima D, Suzuki K, Nishikawa E, Okuno Y, Kawashima N, Nishio N, Masafumi Ito, Kojima S, and Takahashi Y.
  • Organizer: 59th ASH Annual Meeting＆Exposition
  • Int'l Joint Research
• [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, et al.
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] Clinical sequencing of 209 patients with suspected inherited bone marrow failure syndromes (2016)
  • Author(s): Muramatsu H, Okuno Y, Yoshida K, Shiraishi Y, Ogawa S, Miyano S, Kojima S
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] Genetic background of bone marrow failure syndromes in children (2016)
  • Author(s): Narita A, Okuno Y, Muramatsu H, Yoshida K, Shiraishi Y, Sekiya Y, Nishio N, Chiba K, Tanaka H, Wang X, Xu Y, Kawashima N, Doisaki S, Hama A, Takahashi Y, Miyano S, Ogawa S, Ito M, Kojima S
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] Comparison of clinical outcomes between pediatric aplastic anemia and refractory cytopenia of childhood (2016)
  • Author(s): Hama A, Manabe A, Hasegawa D, Nozawa K, Narita A, Muramatsu H, Takahashi Y, Watanabe K, Ohara A, Ito M, Kojima S
  • Organizer: 58th ASH Annual Meeting & Exposition
  • Place of Presentation: サンディエゴ（アメリカ）
  • Int'l Joint Research
• [Presentation] Development of paroxysmal nocturnal hemoglobinuria in children with aplastic anemia (2016)
  • Author(s): Narita A, Muramatsu H, Okuno Y, Sekiya Y, Suzuki K, Hamada M, Kataoka S, Taniguchi R, Ichikawa D, Murakami N, Kojima D, Nishikawa E, Kawashima N, Nishio N, Hama A, Takahashi Y, Kojima S
  • Organizer: 58th ASH Annual Meeting & Exposition
  • Place of Presentation: サンディエゴ（アメリカ）
  • Int'l Joint Research
• [Presentation] Application of next-generation sequencing on bone marrow failure and hematological diseases (2016)
  • Author(s): Muramatsu H
  • Organizer: 第58回日本小児血液・がん学会学術集会
  • Place of Presentation: 品川プリンスホテル（東京都港区）
  • Invited
• [Presentation] Genetic Background of Idiopathic Bone Marrow Failure Syndromes in Children. (2015)
  • Author(s): Atsushi Narita, Yusuke Okuno, Hideki Muramatsu, Kenichi Yoshida, Yuko Sekiya, Kenichi Chiba, Xinan Wang, Nozomu Kawashima, Nobuhiro Nishio, Sayoko Doisaki, Asahito Hama, Yoshiyuki Takahashi, Hirotoshi Sakaguchi, Nao Yoshida, Koji Kato, Satoru Miyano, Masafumi Ito, Seishi Ogawa, Seiji Kojima, et al.
  • Organizer: 58th ASH Annual Meeting & Exposition.
  • Place of Presentation: サン・ディエゴ（米国）
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] 小児特発性骨髄不全症における遺伝的背景 (2015)
  • Author(s): Atsushi Narita, Yusuke Okuno, Hideki Muramatsu, Kenichi Yoshida, Yuichi Shiraishi, Yuko Sekiya, Nobuhiro Nishio, Kenichi Chiba, Hiroko Tanaka, Xinan Wang, Yinyan Xu, Nozomu Kawashima, Sayoko Doisaki, Asahito Hama, Yoshiyuki Takahashi, Satoru Miyano, Seishi Ogawa, Masafumi Ito, Seiji Kojima,
  • Organizer: 第57回日本小児血液・がん学会学術集会
  • Place of Presentation: 山梨県甲府市（甲府富士屋ホテル、常磐ホテル）
  • Year and Date: 2015-11-27
• [Presentation] Development of Paroxysmal Nocturnal Hemoglobinuria in Children with Aplastic Anemia. (2015)
  • Author(s): Atsushi Narita, Hideki Muramatsu, Yusuke Okuno, Yuko Sekiya, Xinan Wang, Norihiro Murakami, Daiei Kojima, Kyogo Suzuki, Nozomu Kawashima, Sayoko Doisaki, Michi Kamei, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, and Seiji Kojima
  • Organizer: 第７７回日本血液学会学術集会
  • Place of Presentation: 石川県金沢市（石川県立音楽堂ANAクラウンプラザホテル金沢、ホテル日航金沢、ホテル金沢、金沢アートホール、もてなしドーム）
  • Year and Date: 2015-10-16
• [Presentation] Target gene sequencing for genetic diagnosis of congenital bone marrow failure syndromes. (2015)
  • Author(s): Yusuke Okuno,Hideki Muramatsu, Kenichi Yoshida, Yuichi Shiraishi, Sayoko Doisaki, Atsushi Narita, Nozomu Kawashima, Xinan Wang, Yinyan Xu, Yuko Sekiya, Kenichi Chiba, Hiroko Tanaka, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, Seishi Ogawa, Satoru Miyano and Seiji Kojima
  • Organizer: 第７７回日本血液学会学術集会
  • Place of Presentation: 石川県金沢市（石川県立音楽堂ANAクラウンプラザホテル金沢、ホテル日航金沢、ホテル金沢、金沢アートホール、もてなしドーム）
  • Year and Date: 2015-10-16
• [Presentation] Genetic background of idiopathic bone marrow failure syndromes in children. (2015)
  • Author(s): Atsushi Narita, Yusuke Okuno, Hideki Muramatsu, Kenichi Yoshida, Yuichi Shiraishi, Yuko Sekiya, Nobuhiro Nishio, Kenichi Chiba, Hiroko Tanaka, Xinan Wang, Yinyan Xu, Nozomu Kawashima, Sayoko Doisaki, Asahito Hama, Yoshiyuki Takahashi, Satoru Miyano, Seishi Ogawa, Masafumi Ito, Seiji Kojima
  • Organizer: the 7th International Symposium on Myelodysplastic syndromes and Bone Marrow Failure.
  • Place of Presentation: オーフス（デンマーク）
  • Year and Date: 2015-10-01
  • Int'l Joint Research
• [Presentation] Target Capture Next Generateio Target Capture Next Generation Sequencing as a Molecular Screening System for Pediatric Bone Marrow Failure Syndromes. (2015)
  • Author(s): Hideki Muramatsu, Yusuke Okuno, Kenichi Yoshida, Sayoko Doisaki, Asahito Hama, Xinan Wang, Atsushi Narita, Nozomu Kawashima, Yinyan Xu, Hirotoshi Sakaguchi, Yoshiyuki Takahashi, Masashi Sanada, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seishi Ogawa, Seiji Kojima
  • Organizer: the 7th International Symposium on Myelodysplastic syndromes and Bone Marrow Failure.
  • Place of Presentation: オーフス（デンマーク）
  • Year and Date: 2015-10-01
  • Int'l Joint Research