Investigation of cis-elements recognized by mutatnt GATA1 by chromation immunoprecipitation sequencing analysis

• Project/Area Number: 25461579
• 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: TOKI Tsutomu 弘前大学, 医学(系)研究科(研究院), 講師 (50195731)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: GATA1 / ダウン症 / 白血病 / ダウン症候群

Outline of Final Research Achievements

About 5% of Down syndrome neonates develop transient abnormal myelopoiesis (TAM). It has been reported that 20% of patients remitted develop acute megakaryoblastic leukemia. Interestingly, almost cases of the disorders harbored mutations in GATA1 gene. The mutations lead to the exclusive expression of a truncated form lacking the N-terminal domain (GATA1s). We aimed to investigate the target genes of GATA1s and to elucidate the pathogenic mechanism of TAM. We focused on three points in this project. First, identification of cis-elements and target genes of GATA1s. Second, investigation of the effect of GATA1s expression level on regulation of target gene expression. Third, probing the responsible domain for development of TAM. In this study, we reported the noble narrower region GATA1 gene for responsible to development of TAM. Next, we proved the increasing the expression of KIT gene by induction of the mutation. We also identified the cis-elements responsible for the up-regulation.

Research Products

• [Journal Article] 非ダウン症小児急性巨核芽球性白血病にみとめられた新規GATA1インフレーム変異 (2014)
  • Author(s): 王汝南, 金崎里香, 土岐力, 照井君典, 佐々木伸也, 工藤耕, 神尾卓哉, 佐藤智彦, 池田史圭, 荒木亮, 落合英俊, 伊藤悦朗
  • Journal Title: 弘前医学 Volume: 65 Pages: 227-237
  • NAID: 110009838312
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Insight into the clonal evolution of Down syndrome-associated myeloid leukemia (2015)
  • Author(s): 土岐 力
  • 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、常磐ホテル（ 山梨県・ 甲府市）
  • Year and Date: 2015-11-27
  • Invited