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

• Project/Area Number: 26461570
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kanegane Hirokazu 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)
• Co-Investigator(Renkei-kenkyūsha): OHARA Osamu 公益財団法人かずさDNA研究所, ヒトゲノム研究部, 副所長 (20370926)
• Research Collaborator: HOSHINO Akihiro
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• 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 Final Research Achievements

We performed whole exome sequencing in patients with possible herediatry lymphoproliferative disorders, and identified NRAS-associated lymphoproliferative disorder, female XIAP deficiency caused by extremely skewed X-chromosome inactivation, aytpical X-linked severe combined immunodeficiency with IL2RG mosaicism, atypical X-linked lymphoproliferative syndrome type 1 with SH2D1A mosaicism, Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) caused by hypomorphic ZAP70 mutation and IKAROS deficiency. It has been proved that EBV-LPD might be associated with at least 23 candidate genes. Therefore, we established comrehensive diagnostic tool by using multiplex PCR and next-generation sequencer.

Research Products

• [Int'l Joint Research] Cincinnati Children’s Hospital(米国)
• [Int'l Joint Research] Institut National de la Sante(France)
• [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 Issue: 5 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: - Issue: 1 Pages: 390-400
  • DOI: 10.1016/j.jaci.2016.09.029
  • Peer Reviewed / Open Access / Int'l Joint Research / 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: - Issue: 6 Pages: 31286-6
  • DOI: 10.1016/j.jaci.2016.09.038
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan. (2017)
  • Author(s): 3.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 Issue: 1 Pages: 85-91
  • DOI: 10.1007/s10875-016-0348-4
  • Peer Reviewed / Open Access
• [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 Issue: 1 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): 5.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 Issue: 10 Pages: 1076-1080
  • DOI: 10.1111/ped.13070
  • Peer Reviewed / Open Access
• [Journal Article] Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. (2016)
  • Author(s): Tsujita Y, et al.
  • Journal Title: J Allergy Clin Immunol. Volume: 138 Issue: 6 Pages: 1672-1680
  • DOI: 10.1016/j.jaci.2016.03.055
  • Peer Reviewed / Int'l Joint Research / 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 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s13045-016-0240-y
• [Journal Article] Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism. (2015)
  • Author(s): Okuno Y, Hoshino A, Muramatsu H, Kawashima N, Wang X, Yoshida K, Wada T, Gunji M, Toma T, Kato T, Shiraishi Y, Iwata A, Hori T, Kitoh T, Chiba K, Tanaka H, Sanada M, Takahashi Y, Nonoyama S, Ito M, Miyano S, Ogawa S, Kojima S, Kanegane H.
  • Journal Title: J Clin Immunol Volume: 35 Issue: 7 Pages: 610-614
  • DOI: 10.1007/s10875-015-0202-0
  • Peer Reviewed
• [Journal Article] Dysgammaglobulinemia Associated With Glu349del, a Hypomorphic XIAP Mutation (2015)
  • Author(s): Nishida N, Yang X, Takasaki I, Imai K, Kato K, Inoue Y, Imamura T, Miyashita R, Kato F, Yamaide A, Mori M, Saito S, Hara J, Adachi Y, Miyawaki T, Kanegane H.
  • Journal Title: J Investig Allergol Clin Immunol Volume: 25 Pages: 205-213
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reduced Numbers and Proapoptotic Features of Mucosal-associated Invariant T Cells as a Characteristic Finding in Patients with Inflammatory Bowel Disease. (2015)
  • Author(s): Hiejima E, Kawai T, Nakase H, Tsuruyama T, Morimoto T, Yasumi T, Taga T, Kanegane H, Hori M, Ohmori K, Higuchi T, Matsuura M, Yoshino T, Ikeuchi H, Kawada K, Sakai Y, Kitazume MT, Hisamatsu T, Chiba T, Nishikomori R, Heike T.
  • Journal Title: Inflamm Bowel Dis Volume: 21 Issue: 7 Pages: 1529-1540
  • DOI: 10.1097/mib.0000000000000397
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Somatic mosaicism for a NRAS mutation associates with disparate clinical features in RAS-associated leukoproliferative disease: a report of two cases. (2015)
  • Author(s): Shiota M, Yang X, Kubokawa M, Morishima T, Tanaka K, Mikami M, Yoshida K, Kikuchi M, Izawa K, Nishikomori R, Okuno Y, Wang X, Sakaguchi H, Muramatsu H, Kojima S, Miyano S, Ogawa S, Takagi M, Hata D, Kanegane H.
  • Journal Title: J Clin Immunol Volume: 35 Issue: 5 Pages: 454-458
  • DOI: 10.1007/s10875-015-0163-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Female Patient with Incomplete Hemophagocytic Lymphohistiocytosis Caused by a Heterozygous XIAP Mutation Associated with Non-Random X-Chromosome Inactivation Skewed Towards the Wild-Type XIAP Allele (2015)
  • Author(s): Yang X, Hoshino A, Taga T, Kunitsu T, Ikeda Y, Yasumi T, Yoshida K, Wada T, Miyake K, Kubota T, Okuno Y, Muramatsu H, Adachi Y, Miyano S, Ogawa S, Kojima S, Kanegane H
  • Journal Title: J Clin Immunol Volume: 35(3) Issue: 3 Pages: 244-8
  • DOI: 10.1007/s10875-015-0144-6
  • Peer Reviewed
• [Journal Article] Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency (2014)
  • Author(s): Wada T, Kanegane H, Ohta K, Katoh F, Imamura T, Nakazawa Y, Miyashita R, Hara J, Hamamoto K, Yang X, Filipovich AH, Marsh RA, Yachie A.
  • Journal Title: Cytokine Volume: 65 Issue: 1 Pages: 74-78
  • DOI: 10.1016/j.cyto.2013.09.007
  • NAID: 120005349175
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children: report from the Japan HLH/LCH Study Group (2014)
  • Author(s): Kogawa K, Sato H, Asano T, Ohga S, Kudo K, Morimoto A, Ohta S, Wakiguchi H, Kanegane H, Oda M, Ishii E
  • Journal Title: Pediatr Blood Cancer Volume: 61 Issue: 7 Pages: 1257-62
  • DOI: 10.1002/pbc.24980
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. (2014)
  • Author(s): Yabal M, Müller N, Adler H, Knies N, Groß CJ, Damgaard RB, Kanegane H, Ringelhan M, Kaufmann T, Heikenwälder M, Strasser A, Groß O, Ruland J, Peschel C, Gyrd-Hansen M, Jost PJ.
  • Journal Title: Cell Rep Volume: 7 Issue: 6 Pages: 1796-1808
  • DOI: 10.1016/j.celrep.2014.05.008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. (2014)
  • Author(s): Aguilar C, Lenoir C, Lambert N, Bègue B, Brousse N, Canioni D, et al.
  • Journal Title: J Allergy Clin Immunol Volume: 134 Issue: 5 Pages: 1131-1141
  • DOI: 10.1016/j.jaci.2014.04.031
  • Peer Reviewed / Acknowledgement Compliant
• [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
  • 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
  • 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
  • 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
  • Int'l Joint Research / Invited
• [Presentation] 10 warning signsから知る原発性免疫不全症 (2016)
  • Author(s): 金兼弘和
  • Organizer: 沖縄小児科学会 第85回例会
  • Place of Presentation: 沖縄県医師会館（南風原市、沖縄県）
  • Year and Date: 2016-03-13
  • Invited
• [Presentation] 免疫不全時の感染症 (2015)
  • Author(s): 金兼弘和
  • Organizer: 第47回日本小児感染症学会
  • Place of Presentation: ザ・セレクトン福島（福島市、福島県）
  • Year and Date: 2015-10-31
• [Presentation] 免疫不全症と感染症 overview (2015)
  • Author(s): 金兼弘和
  • Organizer: 第64回日本感染症学会東日本地方会学術集会
  • Place of Presentation: ロイトン札幌（札幌市、北海道）
  • Year and Date: 2015-10-21
  • Invited
• [Presentation] XLP (X-linked lympho proliferative syndrome) and Epstein-Barr virus infection (2015)
  • Author(s): Kanegane H
  • Organizer: V Simpósio Internacional de Immunodeficiências Primárias—SIDEP
  • Place of Presentation: Belo Horizonte, Brazil
  • Year and Date: 2015-05-22
  • Int'l Joint Research / Invited
• [Presentation] Reemerging subcutaneous immunoglobulin replacement therapy for primary antibody deficiency. (2015)
  • Author(s): Kanegane H
  • Organizer: ASPR Meeting
  • Place of Presentation: 大坂国際会議場（大阪市、大阪府）
  • Year and Date: 2015-04-18
  • Int'l Joint Research / Invited
• [Presentation] Whole exome sequencing reveals atypical phenotype of X-linked lymphoproliferative syndrome. (2014)
  • Author(s): Kanegane H
  • Organizer: A symposium for researchers and clinicians on XLP and WAS
  • Place of Presentation: London, U.K.
  • Year and Date: 2014-11-03 – 2014-11-04
• [Presentation] Inflammatory bowel disease in Japanese patients with XIAP deficiency (2014)
  • Author(s): Nishida N, Yang X, Hoshino A, Kanegane H
  • Organizer: 16th Biennial Meeting of the European Society of Immunodeficiencies
  • Place of Presentation: Prague, Czech
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] Characterization of crohn disease in X-linked inhibitor of apoptosis protein-deficient male patients and female symptomatic carriers (2014)
  • Author(s): Aguilar C, Lenoir C, Lambert N, Begue B, Brousse N, Canioni D, Berrebi D, Roy M, Gerart S, Chapel H, Schwerd T, Siproudhis L, Schappi M, Al-Ahmari A, Yamaide A, Mori M, Galicier L, Neven B, Routes J, Ulhig H, Koletzko S, Patel S, Kanegane H, Picard C, Fischer A, Cerf Bensussan N, Ruemmele F, Hugot J.P, Latour S
  • Organizer: 16th Biennial Meeting of the European Society of Immunodeficiencies
  • Place of Presentation: Prague, Czech
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] X-linked dysgammaglobulinemia associated with somatically reverted memory T cells in a family with X-linked lymphoproliferative syndrome type 1 (2014)
  • Author(s): Yang X, Nishida N, Hoshino A, Goi K, Kanzaki T, Yoshida K, Muramatsu H, Ogawa S, Kojima S, Kanegane H
  • Organizer: 16th Biennial Meeting of the European Society of Immunodeficiencies
  • Place of Presentation: Prague, Czech
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] Female patient with X-linked lymphoproliferative syndrome type 2 caused by extremely skewed inactivation of X-chromosome (2014)
  • Author(s): Yang X, Kunitsu T, Ikeda Y, Taga T, Wada T, Yachie A, Yasumi T, Heike T, Kanegane H
  • Organizer: PAS/ASPR Joint Meeting
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-05-03 – 2014-05-06
• [Presentation] XLP (X-Linked Lymphoproliferative Syndrome) and EB-Virus infection (2014)
  • Author(s): Kanegane H
  • Organizer: PAS/ASPR Joint Meeting
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-05-03 – 2014-05-06
  • Invited
• [Presentation] 女児例を含むXIAP欠損症の同胞例 (2014)
  • Author(s): 國津智彬, 池田勇八, 多賀 崇, 野村明孝, 竹内義博, 松井 潤, 吉田 忍, 八角高裕, 楊 曦, 金兼弘和
  • Organizer: 第117回日本小児科学会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] XIAP欠損症における血清IL-18の持続高値 (2014)
  • Author(s): 和田泰三, 金兼弘和, 太田和秀, 谷内江昭宏
  • Organizer: 第117回日本小児科学会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] NRAS体細胞モザイク変異による自己免疫性リンパ増殖症候群様疾患の１例 (2014)
  • Author(s): 楊 曦, 高木正稔, 菊池雅子, 横田俊平, 小池健一, 村松秀城, 小島勢二, 金兼弘和
  • Organizer: 第117回日本小児科学会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] 原発性免疫不全症に合併する自己炎症 (2014)
  • Author(s): 金兼弘和
  • Organizer: 第117回日本小児科学会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2014-04-11 – 2014-04-13
  • Invited
• [Funded Workshop] 17th Biennial Meeting of the European Society for Immunodeficiencies (ESID) (2016)
  • Place of Presentation: Barcelona
  • Year and Date: 2016-09-21
• [Funded Workshop] XLP-WAS 2016 Symposium-London (2016)
  • Place of Presentation: London