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Modifiers for the Gata1.05 leukemogenesis.

Research Project

Project/Area Number 19H03555
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52010:General internal medicine-related
Research InstitutionTohoku University

Principal Investigator

Shimizu Ritsuko  東北大学, 医学系研究科, 教授 (40226262)

Co-Investigator(Kenkyū-buntansha) 平野 育生  東北大学, 医学系研究科, 講師 (00708117)
長谷川 敦史  東北大学, 医学系研究科, 助教 (80747460)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2022: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2019: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords白血病 / 転写因子 / 遺伝的素因 / 純赤白血病発 / GATA1 / Ras変異 / ドライバー変異 / 純席白血病 / 純赤白血病
Outline of Research at the Start

がんは、環境要因と遺伝的要因とが合わさって発症する多因子疾患と考えられている。詳細な家系解析から、原因遺伝子を含む複数の遺伝的素因が発がんに関与している可能性が蓄積されている。しかし、がん抑制遺伝子やがん原遺伝子などの明かなドライバー変異を除いては、発がんを修飾する遺伝的素因の研究は国内外を通じて全くない。本研究は白血病を自然発症する「家族性腫瘍」モデルマウス系統を用いて、伝統的なマウス遺伝学と先端的なゲノム編集技術や情報解析を組み合わせて、インシデンタルに働く「がん体質」の検証と、「がん体質」とドライバー変異との協調機構の解析を行う独創的な研究である。

Outline of Final Research Achievements

GATA1 is important for differentiation, proliferation and apoptosis of erythropoiesis. We have developed Gata1 knock-down (Gata1.05) allele. Erythroid progenitors of Gata1.05/X female mice, which are heterozygous mice with the Gata1.05 and wildtype alleles, are prone to develop erythroblastic leukemia. The heterozygous mice develop leukemia reproducibly in an approximately 30% frequency, demonstrating the presence of mice that did not develop leukemia, despite harboring preleukemic erythroblasts abundantly in their body. We found in this study that an outbreak of the Gata1.05-driven leukemia was emerged in an autosomal dominant and autosomal recessive manner in 129X1/SvJ and C57BL/6J backgrounds, respectively. We also found that the modifier(s) may be involved in the activation of RAS signaling. To the best of our knowledge, this is the first demonstration of genetic modifiers that alter the outcome of the leukemia-related gene signatures.

Academic Significance and Societal Importance of the Research Achievements

家族内発症疾患の多くにおいてその関連遺伝子が同定され、医療の方向性はゲノム情報に基づく個別化治療・予防に向けて大きく舵を切っている。現在までに多数の白血病関連遺伝子変異が報告されているが、同じ遺伝子型をもつ家族内においても病態の重症度や発症経過が様々であることから、疾患発症を修飾する遺伝的要因の存在も示唆されている。本研究により、定常状態では機能しないが、遺伝的がん関連多型を保持するとき、または、de novo発がんに関わるドライバー変異を獲得したとき、のみに働くインシデンタルな「がん体質」の存在を明らかにした。本研究により「がん体質」の保有の有無による個別化予防についての研究が進むと考える。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (35 results)

All 2023 2022 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (16 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 15 results,  Open Access: 8 results) Presentation (16 results) (of which Int'l Joint Research: 1 results)

  • [Int'l Joint Research] ミシガン大学(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] ミシガン大学(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] ミシガン大学(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Design and Progress of Child Health Assessments at Community Support Centers in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank Project2023

    • Author(s)
      Kobayashi T, Kobayashi M, Minegishi N, Kikuya M, Obara T, Ishikuro M, Yamanaka C, Onuma T, Murakami K, Ueno F, Noda A, Uruno A, Sugawara J, Suzuki K, Kodama EN, Hamanaka Y, Tsuchiya M, Kogure M, Nakaya N, Taira M, Sakurai-Yageta M, Tamahara T, Kawashima J, Goto M, Otsuki A, Shimizu R,Ogishima A,1, Hashizume H, et al.
    • Journal Title

      The Tohoku Journal of Experimental Medicine

      Volume: 259 Issue: 2 Pages: 93-105

    • DOI

      10.1620/tjem.2022.J103

    • ISSN
      0040-8727, 1349-3329
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan2022

    • Author(s)
      Fuse N, Sakurai M, Motoike IN., Kojima K, Takai-Igarashi T, et al.
    • Journal Title

      Ophthalmology Science

      Volume: 2 Issue: 1 Pages: 100113-100113

    • DOI

      10.1016/j.xops.2022.100113

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization and Demonstration of Mock Communities as Control Reagents for Accurate Human Microbiome Community Measurements2022

    • Author(s)
      Tourlousse Dieter M.、Narita Koji、Miura Takamasa、Ohashi Akiko、Matsuda Masami、Ohyama Yoshifumi、Shimamura Mamiko、Furukawa Masataka、Kasahara Ken、Kameyama Keishi、Saito Sakae、Goto Maki、Shimizu Ritsuko、Mishima Riko、Nakayama Jiro、Hosomi Koji、Kunisawa Jun、Terauchi Jun、Sekiguchi Yuji、Kawasaki Hiroko
    • Journal Title

      Microbiology Spectrum

      Volume: 10 Issue: 2

    • DOI

      10.1128/spectrum.01915-21

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding.2022

    • Author(s)
      Hasegawa A, Hayasaka Y, Morita M, Takenaka Y, Hosaka Y, Hirano I, Yamamoto M, Shimizu R.
    • Journal Title

      Commun Biol.

      Volume: - Issue: 1 Pages: 376-376

    • DOI

      10.1038/s42003-022-03316-w

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of <i>Atg2b</i> and <i>Gskip</i> Impairs the Maintenance of the Hematopoietic Stem Cell Pool Size2022

    • Author(s)
      Sakai Shun-suke、Hasegawa Atsushi、Ishimura Ryosuke、Tamura Naoki、Kageyama Shun、Komatsu-Hirota Satoko、Abe Manabu、Ling Yiwei、Okuda Shujiro、Funayama Manabu、Kikkawa Mika、Miura Yoshiki、Sakimura Kenji、Narita Ichiei、Waguri Satoshi、Shimizu Ritsuko、Komatsu Masaaki
    • Journal Title

      Molecular and Cellular Biology

      Volume: 42 Issue: 1 Pages: 1-17

    • DOI

      10.1128/mcb.00024-21

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Study Profile of the Tohoku Medical Megabank Community-Based Cohort Study2021

    • Author(s)
      Hozawa A, Tanno K, Nakaya N, Nakamura T, Tsuchiya N, Hirata T, Narita A, Kogure M, Nochioka K, Sasaki R, Takanashi N, Otsuka K, Sakata K, Kuriyama S, Kikuya M, 13名略, Kobayashi T, 53名略, Yamamoto M.
    • Journal Title

      Journal of Epidemiology

      Volume: 31 Issue: 1 Pages: 65-76

    • DOI

      10.2188/jea.JE20190271

    • NAID

      130007966030

    • ISSN
      0917-5040, 1349-9092
    • Year and Date
      2021-01-05
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oral microbiome analysis in prospective genome cohort studies of the Tohoku Medical Megabank Project2021

    • Author(s)
      Saito S, Aoki Y, Tamahara T, Goto M, Matsui H, Kawashima J, Danjoh I, Hozawa A, Kuriyama S, Suzuki Y, Fuse N, Kure S, Yamashita R, Tanabe O, Minegishi N, Kinoshita K, Tsuboi A, Shimizu R, Yamamoto M.
    • Journal Title

      Front Cell Infect Microbiol.

      Volume: -

    • DOI

      10.3389/fcimb.2020.604596

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blockade of the interaction between BMP9 and endoglin on erythroid progenitors promotes erythropoiesis in mice.2021

    • Author(s)
      Yamaguchi A, Hirano I, Narusawa S, Shimizu K, Ariyama H, Yamawaki K, Nagao K, Yamamoto M, Shimizu R
    • Journal Title

      Gene Cell.

      Volume: 26 Pages: 782-797

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel.2021

    • Author(s)
      Suzuki N, Iwamura Y, Nakai T, Kato K, Otsuki A, Uruno A, Saigusa D, Taguchi K, Suzuki M, Shimizu R, Yumoto A, Okada R, Shirakawa M, Shiba D, Takahashi S, Suzuki T, Yamamoto M
    • Journal Title

      Kidney Int.

      Volume: -

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nrf2 plays a critical role in the metabolic response during and after spaceflight2021

    • Author(s)
      Uruno A、Saigusa D、Suzuki T、Yumoto A、Nakamura T、Matsukawa N、Yamazaki T、Saito R、Taguchi K、Suzuki M、Suzuki N、Otsuki A、Katsuoka F、Hishinuma E、Okada R、Koshiba S、Tomioka Y、Shimizu R、Shirakawa M、Kensler TW.、Shiba D、Yamamoto M
    • Journal Title

      Communications Biology

      Volume: 4 Issue: 1 Pages: 1381

    • DOI

      10.1038/s42003-021-02904-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project.2021

    • Author(s)
      Ogishima S, Nagaie S, 他50名
    • Journal Title

      Human Genome

      Volume: 8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A non-mosaic transchromosomic mouse model of Down syndrome carrying the long arm of human chromosome 212020

    • Author(s)
      Kazuki Yasuhiro、Gao Feng J、Li Yicong、Moyer Anna J、Devenney Benjamin、Hiramatsu Kei、Miyagawa-Tomita Sachiko、Abe Satoshi、Kazuki Kanako、Kajitani Naoyo、Uno Narumi、Takehara Shoko、Takiguchi Masato、Yamakawa Miho、Hasegawa Atsushi、Shimizu Ritsuko、Matsukura Satoko、Noda Naohiro、et al.
    • Journal Title

      eLife

      Volume: 9 Pages: 1-29

    • DOI

      10.7554/elife.56223

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Quantitative and qualitative impairments in GATA2 and myeloid neoplasms2020

    • Author(s)
      Shimizu R, Yamamoto M
    • Journal Title

      IUBMB Life

      Volume: 72 Issue: 1 Pages: 142-150

    • DOI

      10.1002/iub.2188

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GATA factor-related hematopoietic diseases2020

    • Author(s)
      清水律子
    • Journal Title

      Rinsho Ketsueki

      Volume: 61 Issue: 9 Pages: 1112-1119

    • DOI

      10.11406/rinketsu.61.1112

    • NAID

      130007937121

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2020 Annual Research Report
  • [Journal Article] GATA2 hypomorphism induces chronic myelomonocytic leukemia in mice2019

    • Author(s)
      Harada Nobuhiko、Hasegawa Atsushi、Hirano Ikuo、Yamamoto Masayuki、Shimizu Ritsuko
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 4 Pages: 1183-1193

    • DOI

      10.1111/cas.13959

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Generation and Molecular Characterization of Human Ring Sideroblasts: a Key Role of Ferrous Iron in Terminal Erythroid Differentiation and Ring Sideroblast Formation.2019

    • Author(s)
      Saito K, Fujiwara T, Hatta S, Morita M, Ono K, Suzuki C, Fukuhara N, Onishi Y, Nakamura Y, Kawamata S, Shimizu R, Yamamoto M, Harigae H.
    • Journal Title

      Mol Cell Biol.

      Volume: 39 Issue: 7

    • DOI

      10.1128/mcb.00387-18

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] 好塩基球・好酸球数に影響を与える GATA2 遺伝子遠位造血エンハンサーバリアント2023

    • Author(s)
      鈴木未来子、佐藤佳歩 、野本恵莉香、日高高徳、大根田絹子、山本雅之、清水律子
    • Organizer
      第27回造血器腫瘍研究会, 広島大学
    • Related Report
      2022 Annual Research Report
  • [Presentation] 転写因子GATA1による初期赤血球分化制御機構の解析2022

    • Author(s)
      平野育生、Lin Zhang、西羽美、木下賢吾、山本雅之、清水律子.
    • Organizer
      日本生化学会東北支部第88回例会・シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] 赤白血病における転写因子GATA1の機能解析2022

    • Author(s)
      成澤志保、平野育生、Jia Yao、Tsz Ki Yip、芦澤あや、清水律子.
    • Organizer
      日本生化学会東北支部第88回例会・シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] 赤白血病における転写因子GATA1の機能解析2022

    • Author(s)
      成澤志保、平野育生、Jia Yao、Tsz Ki Yip、芦澤あや、清水律子.
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] A Novel murine model for study on GATA1 functions in multi-step megakaryopoiesis.2022

    • Author(s)
      姚佳、平野育生、成澤志保、葉祉其、鈴木未来子、清水律子
    • Organizer
      日本生化学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] The functional analysis of GATA1S in megakaryopoiesis.2022

    • Author(s)
      葉祉其、平野育生、姚佳、成澤志保、芦澤あや、清水律子
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 鎌状赤血球症モデルマウスを用いた血液粘度解析2022

    • Author(s)
      佐藤佳歩、Jia YAO、宍戸信行、山本雅之、清水律子、水上雅史、鈴木未来子、栗原和枝.
    • Organizer
      SMILE Ecoみやぎプロジェクトシンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] Analysis of Blood Viscosity in Sickile Cell Mouse Model2022

    • Author(s)
      Jia YAO, Kaho SATO, Nobuyuki SHISHIDO, Masashi MIZUKAMI, Masayuki YAMAMOTO、Ritsuko SHIMIZU,Mikiko SUZUKI、Kazue KURIHARA
    • Organizer
      SMILE Ecoみやぎプロジェクトシンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] 変異タンパク質によるGATA2の機能障害が惹起する免疫細胞産生異常2022

    • Author(s)
      長谷川敦史, 保坂優奈, 山本雅之, 清水律子
    • Organizer
      第26回造血器腫瘍研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] GATA1発現AML発症マウスモデルの白血病発症機序の解析2022

    • Author(s)
      平野育生、Jia Yao、成澤志保、清水律子
    • Organizer
      第26回造血器腫瘍研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] GATA2変異が引き起こす細胞機能の変化2021

    • Author(s)
      保坂優奈, 長谷川敦史, 山本雅之, 清水律子
    • Organizer
      第87回日本生化学会 東北支部会
    • Related Report
      2021 Annual Research Report
  • [Presentation] GATA2変異に起因する遺伝子発現調節異常の網羅的解析2020

    • Author(s)
      竹中佑太, 長谷川敦史, 清水律子
    • Organizer
      日本生化学会 東北支部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] GATA2変異に起因する遺伝子発現調節異常の網羅的解析2020

    • Author(s)
      竹中佑太, 長谷川敦史, 保坂優奈, 山本雅之, 清水律子
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 赤芽球性白血病発症機序における転写因子GATA1の役割2019

    • Author(s)
      五十嵐友哉、平野育生、佐々木瞳、清水律子
    • Organizer
      第85回 日本生化学会東北支部例会
    • Related Report
      2019 Annual Research Report
  • [Presentation] nalysis of mechanism of erythroblastic leukemia by GATA1 knockdown2019

    • Author(s)
      garashi T, Hirano I, Sasaki H, Shimizu R
    • Organizer
      2019th Tohoku University Thematic Forum for Creativity: Cancer -from Biology to Acceptance-: International symposium 2
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] マウス白血病発症モデルを用いた赤白血病発症に影響を与える遺伝的素因の探索2019

    • Author(s)
      平野育生、田宮元、佐々木瞳、田高周、鈴木美野里、後藤あや、元池育子、木下賢吾、山本雅之、清水律子
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2024-12-25  

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