癌幹細胞の特性維持に関わる長鎖非蛋白コードＲＮＡの同定と新規治療標的としての検討

• Project Area: Development of Novel Treatment Strategies Targeting Cancer Stem Cells
• Project/Area Number: 23130502
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Chiba University
• Principal Investigator: 岩間 厚志 千葉大学, 医学(系)研究科(研究院), 教授 (70244126)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2012: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000); Fiscal Year 2011: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: lincRNA / 白血病幹細胞 / 白血病 / lineRNA / ポリコーム複合体 / MLL-AF9

Outline of Annual Research Achievements

強い転写活性を有する白血病融合蛋白MLL-AF9によって発現が直接活性化されるhuman lincRNAを、ヒト血液細胞株を用いたChIP sequenceとRNA sequence解析によってプロファイリングした。しかし、この細胞系においては主要標的遺伝子座におけるMLL-AF9の十分な結合が得られなかったため、臍帯血CD34+造血幹・前駆細胞をMLL-AF9で形質転換した細胞を用意し、同様の検討を行った。その結果、MLL-AF9の十分な結合が得られ、特異性の高いMLL-AF9の標的遺伝子リストが得られた。すなわち、coding遺伝子174個に加えて、非遺伝子領域に8,000を超えるMLL-AF9の特異的な結合が確認され、この中に多くのlincRNAが含まれるものと考えられた。同時におこなった転写活性化のヒストンマークであるH3K4me3のChIP-sequenceデータと照合することにより、MLL-AF9によって直接転写が活性化されるlincRNAを同定することが可能である。MLL-AF9をはじめとするMLL融合白血病遺伝子によって転写されるlincRNAを絞り込むため、MLL-AF9を持つ急性骨髄性白血病5例と正常核型急性骨髄性白血病5例を用いて、MLL-AF9白血病に特異的なlincRNAをマイクロアレイ (SurePrint G3 Human GE: Agelent社) 解析によってリストアップした。また、ヒトCD34+CD38-造血幹細胞とCD34+CD38+造血前駆細胞のRNA sequenceも終了した。現在、これらのアレイ解析データとRNA sequenceデータを、上記のMLL-AF9結合遺伝子データと照合することにより、MLL-AF9によって直接転写が活性化されるlincRNAを絞り込みつつある。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Role of SOX17 in hematopoietic development from human embryonic stem cells. (2013)
  • Author(s): Nakajima-Takagi Y, Osawa M, Oshima M, Takagi H, Miyagi S, Endoh M, Endo TA, Takayama N, Eto K, Toyoda T, Koseki H, Nakauchi H, Iwama A.
  • Journal Title: Blood. Volume: 121 Issue: 3 Pages: 447-58
  • DOI: 10.1182/blood-2012-05-431403
  • Peer Reviewed
• [Journal Article] Ezh2 augments leukemogenecity by reinforcing differentiation blockage in acute myeloid leukemia (2012)
  • Author(s): Tanaka S
  • Journal Title: Blood Volume: 120 Issue: 5 Pages: 1107-17
  • DOI: 10.1182/blood-2011-11-394932
  • Peer Reviewed
• [Journal Article] Lethal myelofibrosis induced by Bmil-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes (2012)
  • Author(s): Oguro H
  • Journal Title: J Exp Med Volume: 209 Issue: 3 Pages: 445-454
  • DOI: 10.1084/jem.20111709
  • Peer Reviewed
• [Journal Article] 3-Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor-initiating hepatocellular carcinoma cells (2012)
  • Author(s): Chiba T, Suzuki E, Negishi M, Saraya A, Miyagi S, Konuma T, Tanaka S, Tada M, Kanai F, Imazeki F, Iwama A, Yokosuka O
  • Journal Title: International Journal of Cancer Volume: 130(11) Issue: 11 Pages: 2557-2567
  • DOI: 10.1002/ijc.26264
  • Peer Reviewed
• [Journal Article] Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells (2011)
  • Author(s): Mochizuki-Kashio M, Mishima Y, Miyagi S, Negishi M, Saraya A, Konuma T, Shinga J, Koseki H, Iwama A
  • Journal Title: Blood Volume: 118(25) Issue: 25 Pages: 6553-6561
  • DOI: 10.1182/blood-2011-03-340554
  • Peer Reviewed
• [Journal Article] Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche (2011)
  • Author(s): Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S, Taketo MM, Karlsson S, Iwama A, Nakauchi H
  • Journal Title: Cell Volume: 147 Issue: 5 Pages: 1146-1158
  • DOI: 10.1016/j.cell.2011.09.053
  • Peer Reviewed
• [Journal Article] Ex vivo expansion of human hematopoietic stem cells by garcinol, a potent inhibitor of histone acetyltransferase (2011)
  • Author(s): Nishino T, Wang C, Mochizuki-Kashio M, Osawa M, Nakauchi H, Iwama A
  • Journal Title: PLoS One Volume: 6 Issue: 9 Pages: e24298-e24298
  • DOI: 10.1371/journal.pone.0024298
  • Peer Reviewed
• [Journal Article] The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis (2011)
  • Author(s): Mishima Y
  • Journal Title: Blood Volume: 118 Issue: 9 Pages: 2443-2453
  • DOI: 10.1182/blood-2011-01-331892
  • Peer Reviewed
• [Journal Article] Bmil is essential for leukemic reprogramming of myeloid progenitor cells (2011)
  • Author(s): Yuan J
  • Journal Title: Leukemia Volume: 25 Issue: 8 Pages: 1335-1343
  • DOI: 10.1038/leu.2011.85
  • Peer Reviewed
• [Journal Article] Forced expression of the histone demethylase Fbxl10 maintains self-renewing hematopoietic stem cells (2011)
  • Author(s): Konuma T, et al
  • Journal Title: Experimental Hematology Volume: 39(6) Issue: 6 Pages: 697-709
  • DOI: 10.1016/j.exphem.2011.03.008
  • Peer Reviewed
• [Journal Article] Direct activation of Stat5 by ETV6-Lyn fusion protein promotes induction of myeloproliferative neoplasm with myelofibrosis (2011)
  • Author(s): Takeda, et al.
  • Journal Title: British Journal of Haematology Volume: 153 Issue: 5 Pages: 2874-2903
  • DOI: 10.1111/j.1365-2141.2011.08663.x
  • Peer Reviewed
• [Journal Article] Genome-wide analysis of target genes regulated by HoxB4 in hematopoietic stem and progenitor cells developing from embryonic stem cells (2011)
  • Author(s): Oshima
  • Journal Title: Blood Volume: 117 Issue: 15 Pages: e142-e150
  • DOI: 10.1182/blood-2010-12-323212
  • Peer Reviewed
• [Presentation] Role of the polycomb group proteins in the maintenance of hematopoietic stem cells and restriction of tumor development. (2012)
  • Author(s): Iwama A
  • Organizer: The 74th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2012-10-19
  • Invited
• [Presentation] Role of the polycomb group proteins in the maintenance of hematopoietic stem cells and restriction of tumor development. (2012)
  • Author(s): Iwama A
  • Organizer: 41st Annual Scientific Meeting of the ISEH
  • Place of Presentation: Amsterdam, Netherland
  • Year and Date: 2012-08-23
  • Invited
• [Presentation] ヒト造血幹細胞の体外増幅の可能性 (2012)
  • Author(s): 岩間厚志
  • Organizer: 第34回日本造血細胞移植学会総会
  • Place of Presentation: 大阪国際会議場(招待講演)
  • Year and Date: 2012-02-24
• [Presentation] Lethal Myelofibrosis Induced by Bmil-Deficient Hematopoietic Cells Unveils a Tumor Suppres sor Fuction of the Polycomb Group Genes (2011)
  • Author(s): Yuan Jin
  • Organizer: 53^<rd> ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2011-12-12
• [Presentation] Role of Bmil as a tumor suppressor in hematopoiesis (2011)
  • Author(s): 袁〓
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2011-10-15
• [Presentation] ヒト造血幹細胞の体外増幅の可能性 (2011)
  • Author(s): 岩間厚志
  • Organizer: 第21回日本サイトメトリー学会
  • Place of Presentation: 京都市国際交流会館(招待講演)
  • Year and Date: 2011-06-25
• [Presentation] 造血幹細胞のエピジェネティクス (2011)
  • Author(s): 岩間厚志
  • Organizer: 第32回日本炎症・再生医学会
  • Place of Presentation: 国立京都国際会館(招待講演)
  • Year and Date: 2011-06-03