Analysis of leukemogenesis caused by disordered transcription regulation

• Project/Area Number: 24659456
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: SHIMIZU Ritsuko 東北大学, 医学(系)研究科(研究院), 教授 (40226262)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: GATA転写因子 / 遺伝子改変マウス / 白血病 / 巨核球

Research Abstract

GATA1 is a transcription factor essential for erythroid/megakaryocytic cell differentiation. Acquired mutations deleting the N-terminal region of GATA1 protein are frequently found in acute megakaryoblastic leukemia (AMKL) and transient myeloproliferative disorder (TMD) in children with Down syndrome. We found that full length of GATA1 could restrict proliferation of megakaryocyte progenitors derived from livers of GATA1-null fetus and cell line originally established from AMKL patients, whereas mutant GATA1s lacking consensus motif essential for the interaction sites with Rb protein could not support the GATA1 function on the growth regulation of immature megakaryocytes. This finding indicates that the GATA1 function supported by interaction with Rb protein is involved in the onset of TMD.

Research Products

• [Journal Article] PGC-1 Coactivator Activity is Required for Murine Erythropoiesis (2014)
  • Author(s): Cui S, Tanabe O, Lim K-C, Xu HE, Zhou XE, Lin JD, Shi L, Shimizu R, Schmidt L, Campbell A, Yamamoto M, and Engel JD,
  • Journal Title: Mol Cell Biol Volume: 34 Issue: 11 Pages: 1956-1965
  • DOI: 10.1128/mcb.00247-14
  • Peer Reviewed
• [Journal Article] A Remote GATA2 Hematopoietic Enhancer Drives Leukemogenesis in inv(3)(q21 ; q26) by Activating EVI1 Expression (2014)
  • Author(s): Yamazaki H, Suzuki M, Otsuki A, Shimizu R, Bresnick EH, Engel JD, Yamamoto M.
  • Journal Title: Cancer Cell Volume: 25 Issue: 4 Pages: 415-427
  • DOI: 10.1016/j.ccr.2014.02.008
  • Peer Reviewed
• [Journal Article] Keap 1-Nrf2 system regulates cell fate determination of hematopoietic stem cells (2014)
  • Author(s): Murakami S., Shimizu R., Romeo P. H., Yamamoto M. Motohashi H.
  • Journal Title: Genes to Cells Volume: 19 Issue: 3 Pages: 239-253
  • DOI: 10.1111/gtc.12126
  • Peer Reviewed
• [Journal Article] A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. (2014)
  • Author(s): Yamazaki H, Suzuki M, Otsuki A, Shimizu R, Bresnick EH, Engel JD, Yamamoto M. A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression
  • Journal Title: Cancer Cell Volume: in press
  • Peer Reviewed
• [Journal Article] PGC-1 Coactivator Activity is Required for Murine Erythropoiesis. (2014)
  • Author(s): Cui S, Tanabe O, Lim K-C, Xu HE, Zhou XE, Lin JD, Shi L, Shimizu R, Schmidt L, Campbell A, Yamamoto M, Engel JD.
  • Journal Title: Mol Cell Biol Volume: in press
  • Peer Reviewed
• [Journal Article] Loss of a Rho-regulated actin nucleator, mDia2, impairs cytokinesis during mouse fetal erythropoiesis. (2013)
  • Author(s): Watanabe S, De Zan T, Ishizalki T, Yasuda S, Kamijo H, Yamada D, Aoki T, Kiyonari H, Kaneko H, Shimizu R, Yamamoto M, Goshima G, and, Narummiya S
  • Journal Title: Cell Reports Volume: 5(4) Issue: 4 Pages: 926-932
  • DOI: 10.1016/j.celrep.2013.10.021
  • Peer Reviewed
• [Journal Article] Verification of the in vivo activity of three distinct cis-acting elements within the Gatal gene promoter-proximal enhancer in mice (2013)
  • Author(s): Shimizu R, Hasegawa A, Ottolenghi S, Ronchi A, Yamamoto M.
  • Journal Title: Genes to Cells Volume: 18(11) Issue: 11 Pages: 1032-1041
  • DOI: 10.1111/gtc.12096
  • Peer Reviewed
• [Journal Article] GATA factor switching from GATA2 to GATA1 contributes to erythroid differentiation (2013)
  • Author(s): Suzuki M, Kobayashi-Osaki M, Tsutsumi S, Pan X, Ohmori S, Takai J, Moriguchi T, Ohneda O, Ohneda K, Shimizu R, Kanki Y, Kodama T, Aburatani H, Yamamoto M
  • Journal Title: Genes Cells Volume: 18 Issue: 11 Pages: 921-933
  • DOI: 10.1111/gtc.12086
  • Peer Reviewed
• [Journal Article] Establishment of erythroleukemic GAK14 cells and characterization of GATA1 N-terminal domain (2013)
  • Author(s): Mukai HY, Suzuki M, Nagano M, Ohmori S, Otsuki A, Tsuchida K, Moriguchi T, Ohneda K, Shimizu R, Ohneda O, Yamamoto M,
  • Journal Title: Genes Cells Volume: 18 Issue: 10 Pages: 886-898
  • DOI: 10.1111/gtc.12084
  • 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(16) Issue: 16 Pages: 3181-3184
  • DOI: 10.1182/blood-2012-01-405746
  • Peer Reviewed
• [Journal Article] Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling (2013)
  • Author(s): Guiu J, Shimizu R. D'Altri T,Fraser ST, Hatakeyama J, Bresnick EH, Kageyama R, Dzierzak E, Yamamoto M, Espinosa L, Bigas A.
  • Journal Title: J Exp Med Volume: 210(1) Issue: 1 Pages: 71-84
  • DOI: 10.1084/jem.20120993
  • Peer Reviewed
• [Journal Article] The contribution of GATA1 dysfunction to multi-step leukemogenesis (2012)
  • Author(s): Shimizu R, Yamamoto M
  • Journal Title: Cancer Sci Volume: 103(12) Issue: 12 Pages: 2039-2044
  • DOI: 10.1111/cas.12007
  • Peer Reviewed
• [Journal Article] N- and C-terminal transactivation domains of GATA1 protein coordinate hematopoietic program (2012)
  • Author(s): Kaneko H, Kobayashi E, Yamamoto M, Shimizu R
  • Journal Title: J Biol Chem Volume: 287(25) Issue: 25 Pages: 21439-21449
  • DOI: 10.1074/jbc.m112.370437
  • Peer Reviewed
• [Journal Article] UG4 enhancer-driven GATA-2 and bone morphogenetic protein 4 complementation remedies the CAKUT phenotype in Gata2 hypomorphic mutant mice (2012)
  • Author(s): Ainoya K, Moriguchi T, Ohmori S, Souma T, Takai J, Morita M, Chandler KJ, Mortlock DP, Shimizu R, Engel JD, Lim KC, Yamamoto M.
  • Journal Title: Molecular and Cellular Biology Volume: 32 Issue: 12 Pages: 2312-2322
  • DOI: 10.1128/mcb.06699-11
  • Peer Reviewed
• [Journal Article] Mature erythrocyte membrane homeostasis is compromised by loss of the GATA1-FOG1 interaction (2012)
  • Author(s): Hasegawa A, Shimizu R, Mohandas N, Yamamoto M
  • Journal Title: Blood Volume: 119(11) Issue: 11 Pages: 2615-2623
  • DOI: 10.1182/blood-2011-09-382473
  • Peer Reviewed
• [Presentation] Epo遺伝子転写調節領域の探索 (2013)
  • Author(s): 平野育生,鈴木教郎,峯岸直子,山本雅之,清水律子
  • Organizer: 第11回がんとハイポキシア研究会
  • Place of Presentation: 東北大学片平さくらホール(口演・ポスター)
  • Year and Date: 2013-12-13
• [Presentation] GATA2発現低下による単球性白血病の発症メカニズムの解析 (2013)
  • Author(s): 原田伸彦、村田典子、清水律子
  • Organizer: 第24回東北動物実験研究会
  • Place of Presentation: 弘前文化センター弘前(口頭発表、要旨集P8)
  • Year and Date: 2013-12-06
• [Presentation] GATA1アミノ末端側亜鉛フィンガーによるDNA結合親和性調節機構が赤血球分化に果たす役割 (2013)
  • Author(s): 長谷川敦史,金子寛,山本雅之,清水律子
  • Organizer: 日本生化学会東北支部第79回例会
  • Place of Presentation: シンポジウム,東北大学さくらホール,仙台(口頭発表,要旨集p26, No. C-1)
  • Year and Date: 2013-05-11
• [Presentation] 3q21q26症候群におけるEVI1転写活性化と白血病発症の分子機構 (2013)
  • Author(s): 山㟢博未,鈴木未来子,加藤幸一郎,清水律子, James Douglas Engel,山本雅之
  • Organizer: 日本生化学会東北支部第79回例会
  • Place of Presentation: 東北大学さくらホール仙台(ポスター発表,要旨集; p45)
  • Year and Date: 2013-05-11
• [Presentation] 転写因子GATA1の機能異常と多段階白血病発症 (2013)
  • Author(s): 清水律子
  • Organizer: 鳥取大学染色体工学研究センターセミナー
  • Place of Presentation: 鳥取大学
  • Year and Date: 2013-02-22
• [Presentation] 赤血球分化に関わる転写因子GATA1によるROS制御機構の解明 (2013)
  • Author(s): 大槻晃史,金子寛,清水律子,山本雅之
  • Organizer: 東北大学大学院医学系研究科第6回リトリート大学院生研究発表会
  • Place of Presentation: 東北大学さくらホール仙台(ポスター発表,要旨集p 73)
  • Year and Date: 2013-01-19
• [Presentation] 転写因子GATA1による胎児型グロビン遺伝子発現制御機構の解明 (2013)
  • Author(s): 濱中悠賀,鈴木未来子,山㟢博未,清水律子,山本雅之
  • Organizer: 東北大学大学院医学系研究科第6回リトリート大学院生研究発表会
  • Place of Presentation: 東北大学さくらホール仙台(ポスター発表,要旨集p 58)
  • Year and Date: 2013-01-19
• [Presentation] 大槻シス配列に依存したGATA1-DNA結合親和性修飾機構の生理機能解析 (2013)
  • Author(s): 長谷川敦史,清水律子,金子寛,山本雅之
  • Organizer: 東北大学大学院医学系研究科第6回リトリート大学院生研究発表会
  • Place of Presentation: 東北大学さくらホール,仙台(ポスター発表,要旨集p70, No. P-5-E)
  • Year and Date: 2013-01-19
• [Presentation] A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression (2013)
  • Author(s): 山㟢博未,鈴木未来子,加藤幸一郎,大槻晃史,清水律子, James Douglas Engel,山本雅之
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場神戸(ポスター発表,ポスター番号; 3P0852)
• [Presentation] トランスジェニックマウスを利用したエリスロポエチン遺伝子エンハンサーの探索 (2013)
  • Author(s): 平野育生、鈴木教郎、山㟢瞬、峯岸直子、山本雅之、清水律子
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場神戸(ポスター発表, 1P-0195)
• [Presentation] 8染色体逆位モデルマウスを用いたEVI1高発現白血病発症機構の解析 (2013)
  • Author(s): 鈴木未来子,山㟢博未,加藤幸一郎,清水律子, James Douglas Engel,山本雅之
  • Organizer: 第17回造血器腫瘍研究会
  • Place of Presentation: シーガイア・コンベンションセンター宮崎(口頭発表)
• [Presentation] 転写因子GATA1による胎児型グロビン遺伝子発現制御機構の解明 (2013)
  • Author(s): 濱中悠賀,鈴木未来子,山㟢博未,清水律子,山本雅之
  • Organizer: 転写研究会&転写サイクル&転写代謝システム若手ワークショップ
  • Place of Presentation: @鬼怒川,ホテル鬼怒川御苑鬼怒川(ポスター発表,要旨集; p53)
• [Presentation] 3q21q26白血病染色体転座・逆位モデルマウスを用いたEVI1遺伝子転写活性化機構の解析 (2013)
  • Author(s): 鈴木未来子,山㟢博未,加藤幸一郎,清水律子, James Douglas Engel,山本雅之
  • Organizer: 転写研究会&転写サイクル&転写代謝システム若手ワークショップ
  • Place of Presentation: @鬼怒川,ホテル鬼怒川御苑鬼怒川(口頭/ポスター発表,要旨集; p22)
• [Presentation] トランスジェニックマウスを利用したエリスロポエチン遺伝子エンハンサーの探索 (2013)
  • Author(s): 平野育生、鈴木教郎、山崎瞬、峯岸直子、山本雅之、清水律子
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression (2013)
  • Author(s): 山崎博未, 鈴木未来子, 加藤幸一郎, 大槻晃史, 清水律子, James Douglas Engel, 山本雅之
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸国際会議場
• [Presentation] シス配列多様性に依存したGATA1-DNA結合親和性修飾機構の生理機能解析 (2012)
  • Author(s): 長谷川敦史,清水律子,金子寛,黒河博文,山本雅之
  • Organizer: BIA Symposium 2012 (GE Healthcare)
  • Place of Presentation: 明治記念館,東京(ポスター発表, A-3)
  • Year and Date: 2012-07-20
• [Presentation] 多段階白血病発症に関与する転写因子GATA1の機能解析 (2012)
  • Author(s): 清水律子
  • Organizer: 第4回お茶の水セミナー
  • Place of Presentation: 東京ドームホテル、東京
  • Year and Date: 2012-04-18
• [Presentation] DNA binding diversity achieved through the interaction of GATA1 N-finger and GATA motif is important for embryonic erythropoiesis (2012)
  • Author(s): Hasegawa A, Shimizu R, Kurokawa H, Yamamoto M.
  • Organizer: 54^<th> ASH Annual Meeting and Exposition
  • Place of Presentation: Georgia World Congress Center, Atlanta, GA, USA
• [Presentation] シス配列多様性に依存したGATA1-DNA結合親和性修飾機構の生理機能解析 (2012)
  • Author(s): 長谷川敦史,清水律子,金子寛,黒河博文,山本雅之
  • Organizer: 平成24年度「転写代謝システム」領域班会議
  • Place of Presentation: つくばグランドホテル,つくば(ポスター発表, P-18)
• [Presentation] Amino- and Carboxyl-terminal transactivation domains of GATA1 coordinate the hematopoietic program (2012)
  • Author(s): Kaneko H, Eri Kobayashi, Shimizu R, Yamamoto M.
  • Organizer: The 18th Conference on Hemoglobin Switching
  • Place of Presentation: Asiloma Conference Grounds, CA, USA
• [Presentation] Amino- and Carboxyl-terminal transactivation domains of GATA1 coordinate the hematopoietic program (2012)
  • Author(s): Kaneko H, Kobayashi E, Shimizu R, Yamamoto M
  • Organizer: The 18th Conference on Hemoglobin Switching
  • Place of Presentation: Asiloma, USA
• [Presentation] DNA binding diversity achieved through the interaction of GATA1 N-finger and GATA motif is important for embryonic erythropoiesis (2012)
  • Author(s): Hasegawa A, Shimizu R, Kurokawa H, Yamamoto M
  • Organizer: 54th ASH Annual Meeting and Exposition
  • Place of Presentation: Georgia World Congress Center, Atlanta, USA
  • Invited
• [Presentation] シス配列多様性に依存したGATA1-DNA結合親和性修飾機構の生理機能解析 (2012)
  • Author(s): 長谷川 敦史, 清水 律子, 金子 寛, 黒河 博文, 山本 雅之
  • Organizer: 平成24年度「転写代謝システム」領域班会議
  • Place of Presentation: つくばグランドホテル
• [Presentation] 3q21q26症候群におけるEVI1転写活性化と白血病発症の分子機構
  • Author(s): 山崎博未, 鈴木未来子, 加藤幸一郎, 清水律子, James Douglas Engel, 山本雅之
  • Organizer: 日本生化学会東北支部第79回例会
  • Place of Presentation: 東北大学さくらホール
• [Presentation] GATA1アミノ末端側亜鉛フィンガーによるDNA結合親和性調節機構が赤血球分化に果たす役割
  • Author(s): 長谷川敦史, 金子寛, 山本雅之, 清水律子
  • Organizer: 日本生化学会東北支部第79回例会
  • Place of Presentation: 東北大学さくらホール
• [Presentation] ATA2発現低下による単球性白血病の発症メカニズムの解析
  • Author(s): 原田伸彦、村田典子、清水律子
  • Organizer: 第２４回東北動物実験研究会
  • Place of Presentation: 弘前文化センター
• [Presentation] Epo遺伝子転写調節領域の探索
  • Author(s): 平野育生, 鈴木教郎, 峯岸直子, 山本雅之, 清水律子
  • Organizer: 第11回がんとハイポキシア研究会
  • Place of Presentation: 東北大学片平さくらホール
• [Presentation] 多段階白血病発症に関与する転写因子GATA1の機能解析
  • Author(s): 清水律子
  • Organizer: 第4回お茶の水セミナー
  • Place of Presentation: 東京ドームホテル
  • Invited
• [Presentation] シス配列多様性に依存したGATA1-DNA結合親和性修飾機構の生理機能解析
  • Author(s): 長谷川 敦史, 清水 律子, 金子 寛, 黒河 博文, 山本 雅之
  • Organizer: BIA Symposium 2012
  • Place of Presentation: 明治記念館