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

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K09647
• Research Institution: Nagoya University
• Principal Investigator: 村松 秀城 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)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 小児血液学 / 再生不良性貧血

Outline of Annual Research Achievements

HLA一致血縁ドナーが得られない小児再生不良性貧血に対する標準的な治療法は抗胸腺グロブリンとシクロスポリンによる免疫抑制療法であるが、その治療奏効率は40-70%であり、またその反応率を事前に予測することは困難である。近年、非血縁骨髄移植などHLA一致血縁ドナー以外からの造血幹細胞移植の成績が向上してきたことから、初期治療を選択するうえで免疫抑制療法の治療反応予測は臨床的に非常に重要であると考えられる。
我々は、免疫抑制療法で治療した小児再生不良性貧血患者113例の解析を行い、多変量解析でPNH血球陰性・テロメア長短縮がそれぞれ独立した反応不良に関連する因子であることを同定した。この2因子により同定された予後不良群の免疫抑制療法後6か月の反応率はわずかに19%であり、初期治療として非血縁骨髄移植を検討するべき症候群を事前に予測できる可能性が示された（Narita A, Muramatsu H, et al., Haematologica 2015)。また、85例の免疫抑制療法で治療した小児再生不良性貧血患者の診断時の保存血性を用いて各種サイトカイン値を検討したところ、トロンボポイエチン（TPO）値が高値の症例では有意に反応不良であることも示すことができた（Elmahdi S, Muramatsu H, et al., Pediatr Blood Cancer. 2016)。
さらに先天性造血不全に関連した184遺伝子のターゲットシーケンスを開発し（Muramatsu H, et al., Genetics in Medicine 2017)、特発性再生不良性貧血患者181例を対象に実施したところ、26例で関連する遺伝子変異が同定され、先天性造血不全遺伝子のスクリーニングの必要性が示された。

Research Products

• [Journal Article] Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders. (2018)
  • Author(s): Slack J, Albert MH, Balashov D, et al.
  • Journal Title: J Allergy Clin Immunol. Volume: 141(1) Pages: 322-328
  • DOI: 10.1016/j.jaci.2017.02.036
  • Peer Reviewed / Open Access
• [Journal Article] Development of clinical paroxysmal nocturnal haemoglobinuria in children with aplastic anaemia. (2017)
  • Author(s): Narita A, Muramatsu H, Okuno Y, Sekiya Y, Suzuki K, Hamada M, Kataoka S, Ichikawa D, Taniguchi R, Murakami N, Kojima D, Nishikawa E, Kawashima N, Nishio N, Hama A, Takahashi Y, Kojima S.
  • Journal Title: Br J Haematol. Volume: 178(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) Pages: e26419
  • 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, et al.
  • Journal Title: Genet Med. Volume: 19(7) Pages: 796-802
  • DOI: 10.1038/gim.2016.197
  • Peer Reviewed / Open Access
• [Journal Article] Common Variable Immunodeficiency Caused by FANC Mutations. (2017)
  • Author(s): Sekinaka Y, Mitsuiki N, Imai K, et al.
  • Journal Title: J Clin Immunol. Volume: 37(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) Pages: e26305
  • 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(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: 102(3) Pages: e93-e96
  • DOI: 10.3324/haematol.2016.153932
  • 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