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Elucidation of metabolic phenotypes of LICs and development of targeting therapy against LICs through Phd/VHL/HIF-1 regulatory system

Research Project

Project/Area Number 23689049
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionKeio University

Principal Investigator

TAKUBO Keiyo  慶應義塾大学, 医学部, 講師 (50502788)

Project Period (FY) 2011-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥24,700,000 (Direct Cost: ¥19,000,000、Indirect Cost: ¥5,700,000)
Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2013: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Fiscal Year 2011: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Keywords造血幹細胞 / 白血病幹細胞 / 幹細胞ニッチ / メタボロミクス / ニッチ / 低酸素 / メタボローム
Outline of Final Research Achievements

(1) We performed metabolomic analysis in hematopoietic stem cells (HSCs) and found that HSCs generate adenosine-5'-triphosphate by anaerobic glycolysis through a pyruvate dehydrogenase kinase (Pdk)-dependent mechanism. Loss of both Pdk isozymes attenuated HSC phenotypes including cell cycle. Thus, glycolytic metabolic status governed by Pdk acts as a cell cycle checkpoint that modulates HSCs.
(2) Using a CML-like mouse model of myeloproliferative disease, we demonstrate that CML LICs can be divided into CD25(+)FcεRIα(-) Lineage marker (Lin)(-) Sca-1(+)c-Kit(+) (F(-)LSK) cells and CD25(-)F(-)LSK cells. The CD25(+)F(-)LSK cells had multilineage differentiation capacity, with a preference toward cytokine-producing mast cell commitment. The CD25(+)F(-)LSK cells exhibited higher LIC capacity. Our findings suggest that interleukin-2 derived from the microenvironment and CD25 expressed on CML LICs constitute a novel signaling axis that could be preferentially targeted in therapy for CML.

Report

(5 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (41 results)

All 2015 2014 2013 2012 2011 Other

All Journal Article (22 results) (of which Peer Reviewed: 22 results,  Acknowledgement Compliant: 3 results,  Open Access: 3 results) Presentation (15 results) (of which Invited: 3 results) Book (1 results) Remarks (3 results)

  • [Journal Article] Proliferation following tetraploidization regulates the size and number of erythrocytes in the blood flow during medaka development, as revealed by the abnormal karyotype of erythrocytes in the medaka TFDP1 mutant.2015

    • Author(s)
      Taimatsu K, Takubo K, Maruyama K, Suda T, Kudo A.
    • Journal Title

      Dev Dyn.

      Volume: 該当なし Issue: 5 Pages: 651-668

    • DOI

      10.1002/dvdy.24259

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Megakaryocytes are essential for HSC quiescence through the production of thrombopoietin.2014

    • Author(s)
      Nakamura-Ishizu A, Takubo K, Fujioka M, Suda T.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 454 Pages: 353-357

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Tet2-mutated myeloid progenitors possess aberrant in vitro self-renewal capacity.2014

    • Author(s)
      Kunimoto H, Fukuchi Y, Sakurai M, Takubo K, Okamoto S, Nakajima H.
    • Journal Title

      Blood.

      Volume: 123 Issue: 18 Pages: 2897-2899

    • DOI

      10.1182/blood-2014-01-552471

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Telomerase reverse transcriptase has an extratelomeric function in somatic cell reprogramming.2014

    • Author(s)
      Kinoshita T, Nagamatsu G, Saito S, Takubo K, Horimoto K, Suda T.
    • Journal Title

      J Biol Chem.

      Volume: 289 Pages: 15776-15787

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] R-spondins/Lgrs expression in tooth development.2014

    • Author(s)
      Kawasaki M, Porntaveetus T, Kawasaki K, Oommen S, Otsuka-Tanaka Y, Hishinuma M, Nomoto T, Maeda T, Takubo K, Suda T, Sharpe PT, Ohazama A.
    • Journal Title

      Dev Dyn.

      Volume: 243 Issue: 6 Pages: 844-851

    • DOI

      10.1002/dvdy.24124

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The IL-2/CD25 Axis Maintains Distinct Subsets of Chronic M yeloid Leukemia-initiating Cells.2014

    • Author(s)
      Kobayashi CI, Takubo K, Kobayashi H, Nakamura-Ishizu A, Honda H, Kataoka K, Kumano K, Akiyama H, Sudo T, Kurokawa M, Suda T.
    • Journal Title

      Blood

      Volume: 123 Issue: 16 Pages: 2540-2549

    • DOI

      10.1182/blood-2013-07-517847

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Opening the door for HIF1α tuning.2014

    • Author(s)
      Takubo K and Suda T
    • Journal Title

      Blood

      Volume: 123 Issue: 2 Pages: 151-152

    • DOI

      10.1182/blood-2013-11-536995

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function.2014

    • Author(s)
      Nagamachi A, Nakata Y, Ueda T, Yamasaki N, Ebihara Y, Tsuji K, Honda Zi, Takubo K, Suda T, Oda H, Inaba T, Honda H
    • Journal Title

      PLos One

      Volume: 9 Issue: 1 Pages: 1-10

    • DOI

      10.1371/journal.pone.0087425

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7.2013

    • Author(s)
      Nagamachi A
    • Journal Title

      Cancer Cell

      Volume: 24 Issue: 3 Pages: 305-317

    • DOI

      10.1016/j.ccr.2013.08.011

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Induction of pluripotent stem cells by each of the known reprogramming factors from primordial germ cells.2013

    • Author(s)
      Nagamatsu G
    • Journal Title

      Stem Cells

      Volume: 31 Issue: 3 Pages: 479-487

    • DOI

      10.1002/stem.1303

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells.2013

    • Author(s)
      Takubo K
    • Journal Title

      Cell Stem Cell

      Volume: 12 Issue: 1 Pages: 49-61

    • DOI

      10.1016/j.stem.2012.10.011

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prostaglandin E2 regulates murine hematopoietic stem/progenitorcells directly via EP4 receptor and indirectly through mesenchymal progenitor cells.2013

    • Author(s)
      Ikushima YM. Arai F, Hosokawa K, Toyama H, Takubo K, Furuyashiki T, Narumiya S, Suda T
    • Journal Title

      Blood

      Volume: 121(11) Issue: 11 Pages: 1995-2007

    • DOI

      10.1182/blood-2012-06-437889

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Tracing the conversion process for primordial germ cells to pluripotent2012

    • Author(s)
      Nagamatsu G
    • Journal Title

      Biol Reprod

      Volume: 86 Issue: 6 Pages: 182-182

    • DOI

      10.1095/biolreprod.111.096792

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Roles of the hypoxia response system in hematopoietic and leukemic stem cells.2012

    • Author(s)
      Keiyo Takubo
    • Journal Title

      Int J Hematol.

      Volume: 95 Issue: 5 Pages: 478-483

    • DOI

      10.1007/s12185-012-1071-4

    • NAID

      10030632958

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Optimal ratio of transcription factors for somatic cell reprogramming.2012

    • Author(s)
      Nagamatsu G
    • Journal Title

      J Biol Chem

      Volume: 287 Issue: 43 Pages: 36273-36282

    • DOI

      10.1074/jbc.m112.380683

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TAK1 (MAP3K7) signaling regulates hematopoietic stem cells through TNF-dependent and -independent mechanisms2012

    • Author(s)
      Takaesu G, Inagaki M, Takubo K, Mishina Y, Hess PR, Dean GA, Yoshimura A, Matsumoto K, Suda T, Ninomiya-Tsuji J
    • Journal Title

      PLoS One

      Volume: 7(11) Issue: 11 Pages: e51073-e51073

    • DOI

      10.1371/journal.pone.0051073

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dynamic regulation of Th17 differentiation by oxygen concentrations2012

    • Author(s)
      Ai Ikejiri
    • Journal Title

      International Immunology

      Volume: 24 Issue: 3 Pages: 137-146

    • DOI

      10.1093/intimm/dxr111

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In vivo behavior of multiple myeloma cells and their niche in immunodeficient mice2012

    • Author(s)
      Iriuchishima H, Kizaki M, et al
    • Journal Title

      PLoS ONE

      Volume: 7(2) Issue: 2 Pages: e30557-e30557

    • DOI

      10.1371/journal.pone.0030557

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells2011

    • Author(s)
      Taisuke Kinoshita
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 407 Issue: 2 Pages: 321-326

    • DOI

      10.1016/j.bbrc.2011.03.013

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere independent mechanism2011

    • Author(s)
      Nitta Eriko
    • Journal Title

      Blood

      Volume: 117 Issue: 16 Pages: 4169-80

    • DOI

      10.1182/blood-2010-08-297390

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero2011

    • Author(s)
      Kubota Y, Takubo K, Hirashima M, Nagoshi N, Kishi K, Sano K, Murakami M, Ema M, Omatsu Y, Takahashi S, Nagasawa T, Shibuya M, Okano H, Suda T
    • Journal Title

      J Exp Med

      Volume: 208 Issue: 5 Pages: 949-960

    • DOI

      10.1084/jem.20102187

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metabolic regulation of hematopoietic stem cells in the hypoxic niche2011

    • Author(s)
      Suda T, et al
    • Journal Title

      Cell Stem Cell

      Volume: 9 Issue: 4 Pages: 298-310

    • DOI

      10.1016/j.stem.2011.09.010

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] Glycolysis by Pdk maintains the quiescence of hematopoietic stem cells2011

    • Author(s)
      Keiyo Takubo
    • Organizer
      DiSCUSS Meeting
    • Place of Presentation
      MPI-CBG(ドイツ ドレスデン)
    • Year and Date
      2011-12-06
    • Related Report
      2011 Annual Research Report
  • [Presentation] 骨髄腫ニッチの解析2011

    • Author(s)
      田久保圭誉
    • Organizer
      第14回癌と骨病変研究会
    • Place of Presentation
      千代田放送会館(東京)
    • Year and Date
      2011-11-18
    • Related Report
      2011 Annual Research Report
  • [Presentation] Glycolytic Energy Metabolism by Pdk Maintains Quiescence of Hematopoietic Stem Cells2011

    • Author(s)
      田久保圭誉
    • 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(名古屋)
    • Year and Date
      2011-10-15
    • Related Report
      2011 Annual Research Report
  • [Presentation] NOGマウスを用いた多発性骨髄腫と骨髄腫ニッチへのBendamustineの効果の解析2011

    • Author(s)
      田久保圭誉
    • Organizer
      第70回日本癌学会学術総会
    • Place of Presentation
      名古屋国際会議場(名古屋)
    • Year and Date
      2011-10-04
    • Related Report
      2011 Annual Research Report
  • [Presentation] 造血幹細胞の新たな幹細胞性としてのエネルギー代謝制御機構2011

    • Author(s)
      田久保圭誉
    • Organizer
      国立感染症研究所血液・安全性研究部セミナー
    • Place of Presentation
      国立感染症研究所(東京)
    • Year and Date
      2011-09-28
    • Related Report
      2011 Annual Research Report
  • [Presentation] Pdkを介した代謝プログラムによる造血幹細胞維持とその操作2011

    • Author(s)
      田久保圭誉
    • Organizer
      新学術領域「細胞運命制御」若手の会
    • Place of Presentation
      軽井沢プリンスホテル(軽井沢)
    • Year and Date
      2011-09-24
    • Related Report
      2011 Annual Research Report
  • [Presentation] 低酸素応答系による造血幹細胞の代謝プログラム制御機構2011

    • Author(s)
      田久保圭誉
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      国立東都国際会館(京都)
    • Year and Date
      2011-09-22
    • Related Report
      2011 Annual Research Report
  • [Presentation] Anaerobic energy metabolism regulates hematopoietic stem cell quiescence2011

    • Author(s)
      Keiyo Takubo
    • Organizer
      3rd Else Kroner--Fresenius Symposium on Molecular Mechanisms of Adult Stem Cell Aging
    • Place of Presentation
      Reisensburg Castle(ドイツギュンツブルグ)
    • Year and Date
      2011-05-20
    • Related Report
      2011 Annual Research Report
  • [Presentation] Glycolysis maintains quiescence of hematopoietic stem cells2011

    • Author(s)
      Keiyo Takubo
    • Organizer
      Keio University School of Medicine Global COE Program International Symposium 2011 "Cutting Edge of Stem Cell Medicine"
    • Place of Presentation
      慶應義塾大学医学部(東京)
    • Year and Date
      2011-05-16
    • Related Report
      2011 Annual Research Report
  • [Presentation] A protective metabolic program in hematopoietic stem cells2011

    • Author(s)
      Keiyo Takubo
    • Organizer
      第9回幹細胞シンポジウム
    • Place of Presentation
      泉ガーデンギャラリー(東京)
    • Year and Date
      2011-05-14
    • Related Report
      2011 Annual Research Report
  • [Presentation] PROLYL AND ASPARAGINYL HYDROXYLATION IN HYPOXIA-INDUCIBLE FACTOR PLAYS A CRITICAL ROLE IN HEMATOPOIETIC STEM CELL MAINTENANCE

    • Author(s)
      Takubo K
    • Organizer
      ISSCR 11th Annual Meeting
    • Place of Presentation
      Boston
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] ニッチによる造血幹細胞の恒常性制御機構と病態における変容

    • Author(s)
      田久保 圭誉
    • Organizer
      北海道大学大学院歯学研究セミナー
    • Place of Presentation
      北海道大学大学院歯学研究科
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] ニッチによる造血幹細胞の動態制御

    • Author(s)
      田久保 圭誉
    • Organizer
      東京大学分子細胞生物学研究所セミナー
    • Place of Presentation
      東京大学分子細胞生物学研究所
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Regulation of Leukemia Initiating Cells in the Hypoxic CML Niche

    • Author(s)
      Keiyo Takubo
    • Organizer
      第10回幹細胞シンポジウム
    • Place of Presentation
      淡路
    • Related Report
      2012 Annual Research Report
  • [Presentation] Regulation of Leukemia Initiating Cells in the Hypoxic CML Niche

    • Author(s)
      Keiyo Takubo
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      札幌
    • Related Report
      2012 Annual Research Report
  • [Book] Advances in Hematopoietic Stem Cell Research(Edited by Rosana Pelayo)2012

    • Author(s)
      Keiyo Takubo
    • Total Pages
      464
    • Publisher
      InTech
    • Related Report
      2011 Annual Research Report
  • [Remarks] グループウェブサイト

    • URL

      http://www.celldiff.med.keio.ac.jp/taisya.html

    • Related Report
      2013 Annual Research Report
  • [Remarks]

    • URL

      http://web.sc.itc.keio.ac.jp/celldiff/

    • Related Report
      2011 Annual Research Report
  • [Remarks]

    • URL

      http://web.sc.itc.keio.ac.jp/celldiff/taisya.html

    • Related Report
      2011 Annual Research Report

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Published: 2011-04-06   Modified: 2019-07-29  

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