Molecular mechanisms of abnormal cell proliferation in transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591241
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hirosaki University
• Principal Investigator: TERUI Kiminori Hirosaki University, 医学部・附属病院, 講師 (00333740)
• Co-Investigator(Kenkyū-buntansha): TOKI Tsutomu 弘前大学, 大学院・医学研究科, 講師 (50195731)
• Project Period (FY): 2008 – 2010
• Keywords: 小児血液学 / 白血病 / ダウン症候群 / シグナル伝達 / 分子標的療法 / JAK3

Research Abstract

We performed this study to clarify molecular mechanisms of abnormal cell proliferation in transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia of Down syndrome (DS-AMKL), and found the following results.
1. We identified 3 novel JAK3 mutations in a DS-AMKL cell line and a TMD patient, and demonstrated that these mutations were all activating mutations.
2. We showed that JAK3 inhibitors would have therapeutic effects on TMD and DS-AMKL patients carrying activating JAK3 mutations.

Research Products

• [Journal Article] Early and rapid detection of X-linked lymphoproliferative syndrome with SH2D1A mutations by flow cytometry. (2011)
  • Author(s): Zhao M, Kanegane H, Kobayashi C, Nakazawa Y, Ishii E, Kasai M, Terui K, Gocho Y, Imai K, Kiyasu J, Nonoyama S, Miyawaki T
  • Journal Title: Cytometry B Clin Cytom 80 Pages: 8-13
• [Journal Article] Voriconazole for both successful treatment of disseminated Trichosporon asahii infection and subsequent cord blood transplantation in an infant with acute myelogenous leukemia. (2011)
  • Author(s): Kudo K, Terui K, Sasaki S, Kamio T, Sato T, Ito E
  • Journal Title: Bone Marrow Transplant 46 Pages: 310-311
• [Journal Article] Molecular pathogenesis in Diamond-Blackfan anemia. (2010)
  • Author(s): Ito E, Konno Y, Toki T, Terui K
  • Journal Title: Int J Hematol 92 Pages: 413-418
• [Journal Article] Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder : mutation classes correlate with progression to myeloid leukemia. (2010)
  • Author(s): Kanezaki R, Toki T, Terui K, Xu G, Wang R, Shimada A, Hama A, Kanegane H, Kawakami K, Endo M, Hasegawa D, Kogawa K, Adachi S, Ikeda Y, Iwamoto S, Taga T, Kosaka Y, Kojima S, Hayashi Y, Ito E
  • Journal Title: Blood 116 Pages: 4631-4638
• [Journal Article] Guillain-Barre syndrome mimicking acute methotrexate-associated encephalopathy in an adolescent patient with lymphoblastic lymphoma. (2010)
  • Author(s): Terui K, Takahashi Y, Sasaki S, Kudo K, Kamio T, Ito E
  • Journal Title: J Pediatr Hematol Oncol 32 Pages: 615-616
• [Journal Article] PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2. (2010)
  • Author(s): Aikawa Y, Katsumoto T, Zhang P, Shima H, Shino M, Terui K, Ito E, Ohno H, Stanley ER, Singh H, Tenen DG, Kitabayashi I
  • Journal Title: Nat Med 16 Pages: 580-585
• [Journal Article] Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia. (2010)
  • Author(s): Konno Y, Toki T, Tandai S, Xu G, Wang R, Terui K, Ohga S, Hara T, Hama A, Kojima S, Hasegawa D, Kosaka Y, Yanagisawa R, Koike K, Kanai R, Imai T, Hongo T, Park MJ, Sugita K, Ito E
  • Journal Title: Haematologica 95 Pages: 1293-1299
• [Journal Article] Successful umbilical cord blood transplantation for intractable eczematous eruption in hypohidrotic ectodermal dysplasia with immunodeficiency. (2009)
  • Author(s): Minakawa S, Takeda H, Nakano H, Tono C, Takahashi Y, Sasaki S, Terui K, Ito E, Sawamura D
  • Journal Title: Clin Exp Dermatol 34 Pages: e441-442
• [Journal Article] 小児科領域の血液疾患 一過性骨髄増殖性疾患 (2009)
  • Author(s): 伊藤悦朗,土岐力,金崎理香,佐藤知彦,照井君典,足立壮一
  • Journal Title: 日本検査血液学会雑誌 10 Pages: 457-464
• [Journal Article] 一過性骨髄増殖症.小児疾患診療のための病態生理 (2009)
  • Author(s): 土岐力、照井君典、伊藤悦朗
  • Journal Title: 小児内科増刊号 41 Pages: 1183-1186
• [Journal Article] Two novel variants of MOZ-CBP fusion transcripts in spontaneously remitted congenital leukemia with t(1;16;8)(p13;p13;p11), a new variant of t(8;16)(p11;p13). (2008)
  • Author(s): Terui K, Sato T, Kamio T, Kudo K, Sasaki S, Ito E
  • Journal Title: Haematologica 93 Pages: 1591-1593
• [Journal Article] Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome. (2008)
  • Author(s): Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kanegane H, Miura M, Adachi S, Migita M, Morinaga S, Nakano T, Endo M, Kojima S, Kiyoi H, Mano H, Ito E
  • Journal Title: Br J Haematol 141 Pages: 681-688
• [Journal Article] Juvenile myelomonocytic leukemia presenting multiple painful erythematous lesions diagnosed as Sweet's syndrome. (2008)
  • Author(s): Kitamura H, Kaneko T, Nakano H, Terui K, Ito E, Sawamura D
  • Journal Title: J Dermatol 35 Pages: 368-370
• [Journal Article] ダウン症候群に合併する急性巨核芽球性白血病の発症メカニズム (2008)
  • Author(s): 照井君典,伊藤悦朗
  • Journal Title: 血液フロンティア 18 Pages: 83-590
• [Presentation] ダウン症候群に発症する一過性骨髄異常増殖症(TAM)TAMにみられたGATA1遺伝子異常の最近の話題 (2010)
  • Author(s): 土岐力,伊藤悦朗
  • Organizer: 第52回日本小児血液学会
  • Place of Presentation: 大阪
  • Year and Date: 20101217-20101219
• [Presentation] 典型例とは異なる緩徐な臨床経過を示し、リボソームタンパク遺伝子RPL11の変異の検出により診断したDiamond-Blackfan貧血の1例 (2010)
  • Author(s): 佐野弘純,朴明子,外松学,今野友貴,土岐力,伊藤悦朗,林泰秀
  • Organizer: 第52回日本小児血液学会
  • Place of Presentation: 大阪
  • Year and Date: 20101217-20101219
• [Presentation] ダウン症候群に発症する急性骨髄性白血病病理中央診断の解析 (2010)
  • Author(s): 伊藤雅文,木下明俊,多賀崇,宮地勇人,滝智彦,高橋浩之,照井君典,清河信敬,出口隆生,林泰秀,多和昭雄,太田秀明,足立壮一
  • Organizer: 第52回日本小児血液学会
  • Place of Presentation: 大阪
  • Year and Date: 20101217-20101219
• [Presentation] 小児血液疾患の分子診断の進歩とその臨床応用TAM発症の分子診断 (2010)
  • Author(s): 伊藤悦朗,照井君典,佐藤知彦,土岐力
  • Organizer: 第113回日本小児科学会
  • Place of Presentation: 盛岡
  • Year and Date: 20100423-20100425
• [Presentation] Mutations in ribosomal protein genes of Diamond-Blackfan anemia patients in Japan. (2009)
  • Author(s): Konno Y, Toki T, Tandai S, Xu G, Terui K, Ohga S, Kojima S, Yanagisawa R, Koike K, Hasegawa D, Kosaka Y, Kanei R, Imai T, Hongo T, Park MJ, Watanabe A, Ito E
  • Organizer: 51st American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: New Orleans, LA
  • Year and Date: 20091205-20091208
• [Presentation] 17歳発症のAML with multilineage dysplasiaのダウン症例について (2009)
  • Author(s): 清水淳次,多賀崇,堀田真紀子,野村明孝,加藤博文,太田茂,竹内義博,西澤嘉四郎,照井君典
  • Organizer: 第51回日本小児血液学会
  • Place of Presentation: 東京
  • Year and Date: 20091127-20091129
• [Presentation] GATA1、JAK3、JAK2変異を有するダウン症関連急性巨核芽球性白血病由来細胞株(CHYNA)の樹立 (2009)
  • Author(s): 濱麻人,松本公一,土岐力,村松秀城,西尾信博,永田俊人,高橋義行,伊藤悦朗,小島勢二
  • Organizer: 第51回日本小児血液学会
  • Place of Presentation: 東京
  • Year and Date: 20091127-20091129
• [Presentation] 小児血液腫瘍の発症リスクと先天異常 ダウン症候群と血液腫瘍 (2009)
  • Author(s): 土岐力,伊藤悦朗
  • Organizer: 第71回日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 20091023-20091025
• [Presentation] 本邦のDiamond-Blackfan貧血患者におけるリボゾームタンパク遺伝子の変異 (2009)
  • Author(s): 今野友貴,丹代諭,徐剛,土岐力,工藤耕,照井君典,大賀正一,小島勢二,長谷川大一郎,青木由貴,金井理恵,今井剛,本郷輝明,朴明子,柳沢龍,伊藤悦朗
  • Organizer: 第71回日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 20091023-20091025
• [Presentation] 新規KIT選択的阻害剤KI-328の抗白血病細胞効果の検討 (2009)
  • Author(s): 辻村朱音,塩津行正,清井仁,石川裕一,森裕美子,石田広志,新美圭子,土岐力,伊藤悦朗,直江知樹
  • Organizer: 第71回日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 20091023-20091025
• [Presentation] 小児科領域の血液疾患 一過性骨髄増殖性疾患 (2009)
  • Author(s): 伊藤悦朗,土岐力,金崎里香,佐藤知彦,照井君典,足立壮一
  • Organizer: 第10回日本検査血液学会
  • Place of Presentation: 甲府
  • Year and Date: 20090703-20090704
• [Presentation] t(1;16;8)を有する新生児AMLの自然寛解例で認められたMOZ-CBP融合遺伝子の新規variant (2008)
  • Author(s): 照井君典,佐藤知彦,神尾卓哉,工藤耕,佐々木伸也,土岐力,高橋良博,菊地陽,伊藤悦朗
  • Organizer: 第50回日本小児血液学会
  • Place of Presentation: 千葉
  • Year and Date: 20081114-20081116
• [Presentation] ダウン症関連白血病およびTMDにおけるJAK3遺伝子変異の機能解析 (2008)
  • Author(s): 佐藤知彦,土岐力,金崎里香,徐剛,照井君典,金兼弘和,三浦正義,足立壮一,右田昌宏,森永信吾,中野崇秀,遠藤幹也,小島勢二,清井仁,間野博行,伊藤悦朗
  • Organizer: 第70回日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 20081010-20081012
• [Presentation] ダウン症関連白血病細胞の増殖におけるStem cell factor/KITシグナリング (2008)
  • Author(s): 土岐力,金崎里香,足立壮一,徐剛,佐藤知彦,鈴木か, ほり,田内久道,遠藤幹也,伊藤悦朗
  • Organizer: 第70回日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 20081010-20081012
• [Book] 血液腫瘍アトラス 第4版(阿部達生編)(Down症候群患者に発症したM7におけるGATA1遺伝子突然変異) (2009)
  • Author(s): 伊藤悦朗、照井君典
  • Total Pages: 183-186
  • Publisher: 日本医事新報社
• [Remarks] ホームページ等
  • URL: http://www.med.hirosaki-u.ac.jp/~pedia/