Establishment of novel diagnosis and analysis of pathogenesis of herediatry lymphoproliferative disorders

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26461570
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 金兼 弘和 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (00293324)
• Co-Investigator(Kenkyū-buntansha): 廣野 恵一 富山大学, 附属病院, 助教 (80456384)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: X連鎖リンパ増殖症候群 / 自己免疫性リンパ増殖症候群 / SH2D1A / XIAP / NRAS / ZAP70 / IKZF1

Outline of Annual Research Achievements

1）非典型的症状を呈する免疫不全症患者を対象に全エクソーム解析（WES）を行い、NRAS体細胞変異によるRAS関連自己免疫性リンパ増殖症候群様疾患（J Clin Immunol 2015;35:454-8）、X染色体の不活化異常による女性XIAP欠損症（J Clinical Immunol 2015;35:244-8）、IL2RG遺伝子の体細胞モザイクを有するX連鎖重症複合免疫不全症（J Clin Immunol 2015;35:610-4）を同定した。
2）X連鎖劣性遺伝形式を有する低ガンマグロブリン血症の1家系3名の患者を対象にWESを行い、SH2D1A変異を同定し、XLP1(SAP欠損症)と診断した。フローサイトメトリーでメモリーT細胞の一部にSAP陽性細胞を認める体細胞モザイクであった。さらにSAP陽性細胞が機能的に正常であることを証明し、臨床症状の軽症化に関わっていると考えられた。
3）致死的EBV関連リンパ増殖症を呈した男児例を対象にWESを行い、ZAP70変異を同定した。ZAP70変異は通常SCIDを発症するが、今回同定した変異は部分的機能低下型の変異であることを証明した。
4）低ガンマグロブリン血症または自己免疫疾患を呈する6家系9例の患者を対象にWESを行い、IKZF1変異を同定した。同定された変異が機能的に異常であることを証明し、新たな原発性免疫不全症であると提唱した（J Allergy Clin Immmunol 2016 Dec 1[Epub ahead of print]）。
5）EBV関連リンパ増殖症の原因となりうる23の候補遺伝子をマルチプレックスPCRで一度に増幅し、次世代シークエンサーで解析する網羅的診断法を開発した。

Research Products

• [Int'l Joint Research] Cincinnati Children’s Hospital(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Cincinnati Children’s Hospital
• [Int'l Joint Research] Institut National de la Sante(France)
  • Country Name: France
  • Counterpart Institution: Institut National de la Sante
• [Journal Article] HLA haploidentical hematopoietic cell transplantation using clofarabine and busulfan for refractory pediatric hematological malignancy. (2017)
  • Author(s): Takagi M, Ishiwata Y, Aoki Y, Miyamoto S, Hoshino A, Matsumoto K, Nishimura A, Tanaka M, Yanagimachi M, Mitsuiki N, Imai K, Kanegane H, Kajiwara M, Takikawa K, Mae T, Tomita O, Fujimura J, Yasuhara M, Tomizawa D, Mizutani S, Morio T.
  • Journal Title: Int J Hematol Volume: 105 Pages: 686-691
  • DOI: 10.1007/s12185-017-2187-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations (2017)
  • Author(s): Hoshino A, Okada S, Yoshida K, Nishida N, Okuno Y, Ueno H, Yamashita M, Okano T, Tsumura M, Nishimura S, Sakata S, Kobayashi M, Nakamura H, Kamizono J, Mitsui-Sekinaka K, Ichimura T, Ohga S, Nakazawa Y, Takagi M, Imai K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Ogawa S, Kojima S, Nonoyama S, Morio T, Kanegane H.
  • Journal Title: J Allergy Clin Immunol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.jaci.2016.09.029
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome (2017)
  • Author(s): Takagi M, Ogata S, Ueno H, Yoshida K, Yeh T, Hoshino A, Piao J, Yamashita M, Nanya M, Okano T, Kajiwara M, Kanegane H, Muramatsu H, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Bando Y, Kato M, Hayashi Y, Miyano S, Imai K, Ogawa S, Kojima S, Morio T
  • Journal Title: J Allergy Clin Immunol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.jaci.2016.09.038
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan (2017)
  • Author(s): Ono S, Okano T, Hoshino A, Yanagimachi M, Hamamoto K, Nakazawa Y, Imamura T, Onuma M, Niizuma H, Sasahara Y, Tsujimoto H, Wada T, Kunisaki R, Takagi M, Imai K, Morio T, Kanegane H.
  • Journal Title: J Clin Immunol Volume: 37 Pages: 85-91
  • DOI: 10.1007/s10875-016-0348-4
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Targeted Sequencing and Immunological Analysis Reveal the Involvement of Primary Immunodeficiency Genes in Pediatric IBD: a Japanese Multicenter Study (2017)
  • Author(s): Suzuki T, Sasahara Y, Kikuchi A, Kakuta H, Kashiwabara T, Ishige T, Nakayama Y, Tanaka M, Hoshino A, Kanegane H, Abukawa D, Kure S
  • Journal Title: J Clin Immunol Volume: 37 Pages: 67-79
  • DOI: 10.1007/s10875-016-0339-5
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel compound heterozygous mutations in a Japanese girl with Janus kinase 3 deficiency (2016)
  • Author(s): Sato T, Okano T, Tanaka-Kubota M, Kimura S, Miyamoto S, Ono S, Yamashita M, Mitsuiki N, Takagi M, Imai K, Kajiwara M, Ebato T, Ogata S, Oda H, Ohara O, Kanegane H, Morio T
  • Journal Title: Pediatr Int Volume: 58 Pages: 1076-1080
  • DOI: 10.1111/ped.13070
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency (2016)
  • Author(s): Tsujita Y, Mitsui-Sekinaka K, Imai K, Yeh TW, Mitsuiki N, Asano T, Ohnishi H, Kato Z, Sekinaka Y, Zaha K, Kato T, Okano T, Takashima T, Kobayashi K, Kimura M, Kunitsu T, Maruo Y, Kanegane H, et al.
  • Journal Title: J Allergy Clin Immunol Volume: 138 Pages: 1672-1680
  • DOI: 10.1016/j.jaci.2016.03.055
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Allogeneic stem cell transplantation for X-linked agammaglobulinemia using reduced intensity conditioning as a model of the reconstitution of humoral immunity (2016)
  • Author(s): Ikegame K, Imai K, Yamashita M, Hoshino A, Kanegane H, Morio T, Kaida K, Inoue T, Soma T, Tamaki H, Okada M, Ogawa H
  • Journal Title: J Hematol Oncol Volume: 9 Pages: 9
  • DOI: 10.1186/s13045-016-0240-y
• [Presentation] Recent advances in primary antibody immunodeficiency and immunoglobulin replacement therapy (2016)
  • Author(s): Kanegane H
  • Organizer: 21th Congress of Chinese Pediatric Society
  • Place of Presentation: Zhuhai (Main China)
  • Year and Date: 2016-10-23 – 2016-10-24
  • Int'l Joint Research / Invited
• [Presentation] 原発性免疫不全症と血液学 (2016)
  • Author(s): 金兼弘和
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜市 (日本)
  • Year and Date: 2016-10-13 – 2016-10-15
  • Invited
• [Presentation] Selective dysregulation of Epstein Barr virus infection in hypomorphic ZAP70 mutation (2016)
  • Author(s): 26.Kanegane H, Hoshino A, Takashima T, Yeh T-W, Okano T, Yamashita M, Imai K, Morio T
  • Organizer: XLP-WAS 2016 Symposium
  • Place of Presentation: London （United Kingdom）
  • Year and Date: 2016-09-26
  • Int'l Joint Research
• [Presentation] Use of flow cytometry in PID diagnosis (2016)
  • Author(s): Kanegane H
  • Organizer: APSID Main Congress
  • Place of Presentation: Hong Kong （Main China)
  • Year and Date: 2016-04-29 – 2016-05-01
  • Int'l Joint Research / Invited
• [Presentation] Immunoglobulin replacement for agammaglobulinemia - intravenous or subcutanesou? (2016)
  • Author(s): Kanegane H
  • Organizer: APSID Main Congress
  • Place of Presentation: Hong Kong (Main China)
  • Year and Date: 2016-04-29 – 2016-05-01
  • Int'l Joint Research / Invited
• [Funded Workshop] XLP-WAS 2016 Symposium-London (2016)
  • Place of Presentation: London
  • Year and Date: 2016-09-26 – 2016-09-26
• [Funded Workshop] 17th Biennial Meeting of the European Society for Immunodeficiencies (ESID) (2016)
  • Place of Presentation: Barcelona
  • Year and Date: 2016-09-21 – 2016-09-24