Molecular mechanisms of development of Down syndrome-associated acute lymphoblastic leukemia and novel therapeutic targets for this disease

• Project/Area Number: 26461560
• 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, 医学研究科, 准教授 (00333740)
• Co-Investigator(Kenkyū-buntansha): 土岐 力 弘前大学, 医学研究科, 講師 (50195731)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ダウン症候群 / 急性リンパ性白血病 / レセプターチロシンキナーゼ / RAS / CRLF2 / JAK / 分子標的治療 / エピゲノム / シグナル伝達 / FLT3 / JAK2 / コヒーシン

Outline of Final Research Achievements

We performed this study to clarify molecular mechanisms of development of Down syndrome-associated acute lymphoblastic leukemia (DS-ALL)and to find novel therapeutic targets, and obtained the following results.
1. Gene alterations in the receptor tyrosine kinase (RTK)-RAS and the CRLF2-JAK pathways were found in about 40% and 20% of Japanese DS-ALL patients, respectively, and they were mutually exclusive. It is suggested that these pathways are potential therapeutic targets.
2. Gene mutations in epigenetic regurators were found in about half of Japanese DS-ALL patients lacking both RTK-RAS and CRLF2-JAK pathway mutations. Epigenetic agents may be useful for these patients.

Research Products

• [Journal Article] Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan. (2014)
  • Author(s): Hanada I, Terui K, Ikeda F, Toki T, Kanezaki R, Sato T, Kamio T, Kudo K, Sasaki S, Takahashi Y, Hayashi Y, Inukai T, Kojima S, Koike K, Kosaka Y, Kobayashi M, Imaizumi M, Mitsui T, Hori H, Hara J, Horibe K, Nagai J, Goto H, Ito E.
  • Journal Title: Genes Chromosomes Cancer Volume: 53 Issue: 11 Pages: 902-910
  • DOI: 10.1002/gcc.22201
  • Peer Reviewed / Open Access
• [Presentation] ダウン症候群児における急性リンパ性白血病のメチル化解析 (2016)
  • Author(s): 久保田 泰央, 瓜生 久美子, 河合 智子, 伊東 竜也, 花田 勇, 土岐 力, 関 正史, 吉田 健一, 佐藤 悠佑, 白石 友一, 千葉 健一, 田中 洋子, 宮野 悟, 岡 明, 林 泰英, 小川 誠司, 照井 君典, 佐藤 篤, 秦 健一郎, 伊藤 悦朗, 滝田 順子
  • Organizer: 第58回日本小児血液・がん学会学術集会
  • Place of Presentation: 品川プリンスホテル（東京都）
  • Year and Date: 2016-12-15
• [Presentation] 小児急性リンパ性白血病再発例に頻発するRAS経路の体細胞突然変異 (2016)
  • Author(s): 久保 かほり, 土岐 力, 金崎 里香, 伊東 竜也, 池田 史圭, 佐藤 知彦, 神尾 卓哉, 工藤 耕, 佐々木 伸也, 照井 君典, 伊藤 悦朗
  • Organizer: 第58回日本小児血液・がん学会学術集会
  • Place of Presentation: 品川プリンスホテル（東京都）
  • Year and Date: 2016-12-15
• [Presentation] Gene expression profiles and methylation analysis in Down syndrome related acute lymphoblastic leukemia (2016)
  • Author(s): Kubota Y, Uryu K, Kawai T, Ito T, Hanada I, Toki T, Seki M, Yoshida K, Kataoka K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Oka A, Hayashi Y, Ogawa S, Terui K, Sato A, Hata K, Ito E and Takita J
  • Organizer: 58th American Society of Hematology Annual Meeting
  • Place of Presentation: San Diego, United States of America
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] RAS pathway mutations in Down syndrome-associated acute lymphoblastic leukemia in Japan (2015)
  • Author(s): Ito T, Terui K, Hanada I, Ikeda F, Toki T, Kanezaki R, Sato T, Kamio T, Kudo K, Sasaki S, Takahashi Y, Hayashi Y, Inukai T, Hori H and Ito E
  • Organizer: 57th American Sciety of Hematology Annual Meeting
  • Place of Presentation: Orlando, United States of America
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] ダウン症候群関連急性リンパ性白血病におけるRAS経路の遺伝子変異 (2015)
  • Author(s): 伊東 竜也, 照井 君典, 花田 勇, 池田 史佳, 土岐 力, 金崎 里香, 佐藤 知彦, 神尾 卓哉, 工藤 耕, 佐々木 伸也, 高橋 良博, 林 泰秀, 犬飼 岳史, 堀 浩樹, 伊藤 悦朗
  • Organizer: 第57回日本小児血液・がん学会学術集会
  • Place of Presentation: 甲府富士屋ホテル（山梨県・甲府市）
  • Year and Date: 2015-11-27
• [Presentation] Gene alterations in Down syndrome-associated acute lymphoblastic leukemia in Japan (2015)
  • Author(s): Terui K, Hanada I, Ikeda F, Ito T, Toki T, Kanezaki R, Sato T, Kamio T, Kudo K, Sasaki S, Takahashi Y, Hayashi Y, Inukai T, Hori H, Ito E
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂外（石川県・金沢市）
  • Year and Date: 2015-10-16