Molecular mechanisms of abnormal cell proliferation in acute lymphoblastic leukemia of Down syndrome

• Project/Area Number: 23591527
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hirosaki University
• Principal Investigator: TERUI KIMINORI 弘前大学, 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): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ダウン症候群 / 急性リンパ性白血病 / JAK2 / CRLF2 / 分子標的治療 / EBF1 / IKZF1 / BTG1

Research Abstract

We performed this study to clarify molecular mechanisms of abnormal cell proliferation in acute lymphoblastic leukemia of Down syndrome (DS-ALL) in Japan, and found the following results.
1. The frequencies of genetic alterations involving the CRLF2-JAK pathway in Japanese DS-ALL patients were slightly lower than those in Western countries. There may be other important pathways involved in pathogenesis of DS-ALL in Japan.
2. EBF1 deletions were found at an unexpectedly high frequency, and associated with the P2RY8-CRLF2 fusion. It is suggested that P2RY8-CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS-ALL patients.

Research Products

• [Journal Article] Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity : a collaborative study by the International-Berlin-Frankfurt-Munst er AML-study group (2013)
  • Author(s): Coenen EA, Zwaan CM, Reinhardt D, Harrison CJ, Haas OA, de Haas V, Mihál V, De Moerloose B, Jeison M, Rubnitz JE, Tomizawa D, Johnston D, Alonzo TA, Hasle H, Auvrignon A, Dworzak M, Pession A, van der Velden VH, Swansbury J, Wong KF, Terui K, Savasan S, Winstanley M, Vaitkeviciene G, Zimmermann M, Pieters R, van den Heuvel-Eibrink MM.
  • Journal Title: Blood Volume: 122 Pages: 2704-13
  • Peer Reviewed
• [Journal Article] Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children (2013)
  • Author(s): Tomizawa D, Tawa A, Watanabe T, Saito AM, Kudo K, Taga T, Iwamoto S, Shimada A, Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Koh K, Kigasawa H, Kosaka Y, Miyachi H, Horibe K, Nakahata T, Adachi S.
  • Journal Title: Leukemia Volume: 12 Pages: 2413-6
  • Peer Reviewed
• [Journal Article] The landscape of somatic mutations in Down syndrome-related myeloid disorders (2013)
  • Author(s): Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, Sanada M, Park MJ, Terui K, Suzuki H, Kon A, Nagata Y, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kato K, Nishimura R, Izraeli S, Hayashi Y, Miyano S, Kojima S, Ito E, Ogawa S.
  • Journal Title: Nat Genet Volume: 45 Pages: 1293-9
  • Peer Reviewed
• [Journal Article] Appropriate dose reduction in induction therapy is essential for the treatment of infants with acute myeloid leukemia : a report from the Japanese Pediatric Leukemia/Lymphoma Study Group (2013)
  • Author(s): Tomizawa D, Tawa A, Watanabe T, Saito AM, Kudo K, Taga T, Iwamoto S, Shimada A, Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Kiyokawa N, Isoyama K, Mizutani S, Hara J, Horibe K, Nakahata T, Adachi S.
  • Journal Title: Int J Hematol Volume: 98 Pages: 578-88
  • Peer Reviewed
• [Journal Article] Clinical characteristics and outcomes of chédiak-Higashi syndrome : A nationwide survey of Japan (2013)
  • Author(s): Nagai K, Ochi F, Terui K, Maeda M, Ohga S, Kanegane H, Kitoh T, Kogawa K, Suzuki N, Ohta S, Ishida Y, Okamura T, Wakiguchi H, Yasukawa M, Ishii E.
  • Journal Title: Pediatr Blood Cancer Volume: 60 Pages: 1582-6
  • Peer Reviewed
• [Journal Article] Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome (2013)
  • Author(s): Saida S, Watanabe K, Sato-Otsubo A, Terui K, Yoshida K, Okuno Y, Toki T, Wang R, Shiraishi Y, Miyano S, Kato I, Morishima T, Fujino H, Umeda K, Hiramatsu H, Adachi S, Ito E, Ogawa S, Ito M, Nakahata T, Heike T.
  • Journal Title: Blood Volume: 121 Pages: 4377-87
  • Peer Reviewed
• [Journal Article] Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome (2013)
  • Author(s): Toki T, Kanezaki R, Kobayashi E, Kaneko H, Suzuki M, Wang R, Terui K, Kanegane H, Maeda M, Endo M, Mizuochi T, Adachi S, Hayashi Y, Yamamoto M, Shimizu R, Ito E.
  • Journal Title: Blood Volume: 121 Pages: 3181-4
  • Peer Reviewed
• [Journal Article] ダウン症候群関連急性リンパ性白血病におけるJAK2およびCRLF2遺伝子異常 (2013)
  • Author(s): 照井君典,花田勇,土岐力,伊藤悦朗
  • Journal Title: 日本小児血液・がん学会雑誌 Volume: 50 Pages: 11-14
• [Journal Article] 新生児科医のためのTAM診療ガイドラインTAM発症の分子機構 (2013)
  • Author(s): 伊藤悦朗,金崎理香,王汝南,照井君典,土岐力
  • Journal Title: 日本周産期・新生児医学会雑誌 Volume: 49 Pages: 20-22
• [Journal Article] Down syndrome associated myeloid disorders (2013)
  • Author(s): 伊藤悦朗,土岐力
  • Journal Title: 血液フロンティア Volume: 24 Pages: 47-53
• [Journal Article] Japan Association of Childhood Leukaemia Study. Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003-06 from the Japan Association of Childhood Leukaemia Study (2012)
  • Author(s): Imamura T, Iwamoto S, Kanai R, Shimada A, Terui K, Osugi Y, Kobayashi R, Tawa A, Kosaka Y, Kato K, Hori H, Horibe K, Oda M, Adachi S
  • Journal Title: Br J Haematol Volume: 159 Pages: 204-10
  • Peer Reviewed
• [Journal Article] Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome (2012)
  • Author(s): Taga T, Saito AM, Kudo K, Tomizawa D, Terui K, Moritake H, Kinoshita A, Iwamoto S, Nakayama H, Takahashi H, Tawa A, Shimada A, Taki T, Kigasawa H, Koh K, Adachi S.
  • Journal Title: Blood Volume: 120 Pages: 1810-5
  • Peer Reviewed
• [Journal Article] Clinical features and outcome of X-linked lymphoproliferative syndrome type 1 (SAP deficiency) in Japan identified by the combination of flow cytometric assay and genetic analysis (2012)
  • Author(s): Kanegane H, Yang X, Zhao M, Yamato K, Inoue M, Hamamoto K, Kobayashi C, Hosono A, Ito Y, Nakazawa Y, Terui K, Kogawa K, Ishii E, Sumazaki R, Miyawaki T.
  • Journal Title: Pediatr Allergy Immunol Volume: 23 Pages: 488-493
  • Peer Reviewed
• [Journal Article] Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia (2012)
  • Author(s): Kuramitsu M, Sato-Otsubo A, Morio T, Takagi M, Toki T, Terui K, Wang R, Kanno H, Ohga S, Ohara A, Kojima S, Kitoh T, Goi K, Kudo K, Matsubayashi T, Mizue N, Ozeki M, Masumi A, Momose H, Takizawa K, Mizukami T, Yamaguchi K, Ogawa S, Ito E, Hamaguchi I.
  • Journal Title: Blood Volume: 119 Pages: 2376-84
  • Peer Reviewed
• [Journal Article] A novel mutation of ribosomal protein S10 gene in a Japanese patient with diamond-Blackfan anemia (2012)
  • Author(s): Yazaki M, Kamei M, Ito Y, Konno Y, Wang R, Toki T, Ito E.
  • Journal Title: J Pediatr Hematol Oncol Volume: 34 Pages: 293-5
  • Peer Reviewed
• [Journal Article] Down症に伴う骨髄増殖症 (2012)
  • Author(s): 伊藤悦朗,土岐力
  • Journal Title: 日本臨床 Volume: 70 Pages: 687-91
• [Journal Article] CD7-positive acute myelomonocytic leukemia with trisomy 21 as a sole acquired chromosomal abnormality in two adolescents (2011)
  • Author(s): Kudo K, Terui K, Sasaki S, Kamio T, Sato T, Ito E.
  • Journal Title: Leuk Res Volume: 35
  • Peer Reviewed
• [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 Volume: 80 Pages: 8-13
  • Peer Reviewed
• [Journal Article] 一過性骨髄異常増殖症(TAM)発症の分子機構 (2011)
  • Author(s): 土岐力,伊藤悦朗
  • Journal Title: 日本小児血液学会雑誌 Volume: 25 Pages: 171-8
• [Presentation] Genetic basis of myeloid proliferation related to Down syndrome (2012)
  • Author(s): Yoshida K, Toki T, Park MJ, Okuno Y, Shiraishi Y, Sanada M, Kon A, Nagata Y, Sato-Otsubo A, Sato Y, Wang RN, Terui K, Kanezaki R, Shiba N, Chiba K, Tanaka H, Hama A, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Miyano S, Kojima S, Izraeli S, Hayashi Y, Ito E, and Ogawa S.
  • Organizer: 54th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Atlanta, GA.
• [Presentation] NOGマウスを用いたTAMの病態解析 (2012)
  • Author(s): 才田聡,渡邉健一郎,佐藤亜以子,照井君典,吉田健一,奥野友介,土岐力,王汝南,白石友一,宮野悟,加藤格,森嶋達也,梅田雄嗣,平松英文,藤野寿典,足立壮一,丹羽明,中畑龍俊,伊藤悦朗,小川誠司,平家俊男
  • Organizer: 第54回日本小児血液・がん学会学術集会
  • Place of Presentation: 横浜
• [Presentation] 新生児科医のためのTAM診療ガイドラインTAM発症の分子機構 (2012)
  • Author(s): 伊藤悦朗,金崎理香,王汝南,照井君典,土岐力
  • Organizer: 第48回日本周産期・新生児医学会学術集会
  • Place of Presentation: 大宮市
• [Presentation] 小児科悪性腫瘍Down症候群に伴うTAM発症の分子機構 (2012)
  • Author(s): 伊藤悦朗,金崎里香,王汝南,佐藤知彦,照井君典,土岐力
  • Organizer: 第22回日本産婦人科・新生児血液学会学術集会
  • Place of Presentation: 津市
• [Presentation] JAK2 mutations and CRLF2 rearrangements in Down syndrome-associated acute lymphoblastic leukemia in Japan (2011)
  • Author(s): Hanada I, Terui K, Toki T, Kudo K, Sato T, Kamio T, Sasaki S, Takahashi Y, Hayashi Y, Sugita K, Kojima S, Koike K, Kosaka Y, Kobayashi M, and Ito E.
  • Organizer: 53th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: San Diego, CA
• [Presentation] GATA1 mutants lacking Rb-binding motif observed in transient abnormal myelopoiesis in Down syndrome (2011)
  • Author(s): Toki T, Kobayashi E, Kanezaki R, Wang RN, Terui K, Kanegane H, Maeda M, Endo M, Mizuochi T, Adachi S, Hayashi Y, Shimizu R, Yamamoto M, and Ito E.
  • Organizer: 53th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: San Diego, CA
• [Presentation] 小児ALLにおけるCRLF2、IKZF1、JAK2遺伝子の臨床的意義ダウン症候群関連ALLの発症におけるJAK2、およびCRLF2遺伝子異常の解析 (2011)
  • Author(s): 花田勇,照井君典,土岐力,工藤耕,佐藤知彦,神尾卓哉,佐々木伸也,高橋良博,林泰秀,杉田完爾,小島勢二,小池健一,小阪嘉之,小林正夫,伊藤悦朗
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋
• [Presentation] ダウン症候群に合併した一過性骨髄増殖症(TAM)および急性巨核芽球性白血病(AMKL)の全エクソンシーケンス (2011)
  • Author(s): 吉田健一,土岐力,朴明子,永田安伸,王汝南,白石友一,真田昌,昆彩菜,佐藤亜衣子,長崎正朗,宮野悟,金兼弘和,川上清,加藤剛二,小島勢二,林泰秀,伊藤悦朗,小川誠司
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋
• [Presentation] ダウン症候群に発症した急性骨髄性白血病(AML-DS)の寛解導入不能・再発例の多施設共同後方視的研究 (2011)
  • Author(s): 多賀崇,齋藤明子,工藤寿子,富澤大輔,照井君典,盛武浩,木下明俊,岩本彰太郎,中山秀樹,高橋浩之,多和昭雄,嶋田明,気賀沢寿人,康勝好,滝智彦,足立壮一, JPLSG AML委員会
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋
• [Presentation] JAK2 mutations and CRLF2 rearrangements in Down syndrome-associated acute lymphoblastic leukemia in Japan. (2011)
  • Author(s): Hanada I, Terui K, Toki T, Kudo K, Sato T, Kamio T, Sasaki S, Takahashi Y, Hayashi Y, Sugita K, Kojima S, Koike K, Kosaka Y, Kobayashi M, and Ito E.
  • Organizer: 53rd American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: San Diego
• [Presentation] ダウン症候群関連ALLにおけるJAK2およびCRLF2遺伝子異常の解析 (2011)
  • Author(s): 花田勇、照井君典、土岐力、工藤耕、佐藤知彦、神尾卓哉、佐々木伸也、高橋良博、林泰秀、杉田完爾、小島勢二、小池健一、小阪嘉之、小林正夫、伊藤悦朗
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 前橋市
• [Book] ダウン症に合併した一過性骨髄異常増殖症におけるGATA1変異と急性白血病への進展. Annual Review血液2012.高久史麿ら編 (2012)
  • Author(s): 土岐力,伊藤悦朗
  • Publisher: 中外医学社
• [Remarks]
  • URL: http://www.med.hirosaki-u.ac.jp/~pedia/index.html