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Establishment of the myeloid leukemic stem cell-targeted therapy

Research Project

Project/Area Number 25253069
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKyushu University

Principal Investigator

Akashi Koichi  九州大学, 医学(系)研究科(研究院), 教授 (80380385)

Co-Investigator(Kenkyū-buntansha) Miyamoto Toshihiro  九州大学, 大学院医学研究院 病態修復内科学, 講師 (70343324)
Iwasaki Hiromi  九州大学病院, 遺伝子細胞療法部, 准教授 (20403925)
Takenaka Katsuto  九州大学病院, 遺伝子細胞療法部, 講師 (30301295)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥45,110,000 (Direct Cost: ¥34,700,000、Indirect Cost: ¥10,410,000)
Fiscal Year 2015: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
Fiscal Year 2014: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
Fiscal Year 2013: ¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000)
Keywordsがん幹細胞 / 白血病幹細胞 / 免疫不全マウス / TIM-3 / 癌幹細胞 / 骨髄増殖性腫瘍 / 骨髄異形成症候群 / 分子標的治療
Outline of Final Research Achievements

In this study, we have identified common machinery for the development and maintenance of myeloid leukemic stem cells; TIM-3/galectin-9 autocrine loop. CD34+CD38-TIM-3+ myeloid leukemic stem cells produce and secrete galectin-9, TIM-3 ligand in an autocrine manner, leading to the constitutive activation of TIM-3 signaling. TIM-3 signaling promotes self-renewal capacity of the malignant stem cells via co-activation of NF-kB and beta-catenin pathways. Thus, signaling molecules downstream of TIM-3 and galectin-9 ligation, as well as surface TIM-3 itself might be good candidates for cancer stem cell-target therapy common to most myeloid malignancies. In addition to the identification of TIM-3/galectin-9 autocrine loop, we established the novel immunodeficient mice lines; BRGS and BRGSK mice. Human normal and malignant hematopoiesis could be efficiently reconstituted in the novel immunodeficient mice.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (31 results)

All 2016 2015 2014 2013 Other

All Journal Article (14 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 14 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (14 results) (of which Int'l Joint Research: 2 results,  Invited: 5 results) Remarks (3 results)

  • [Journal Article] Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes.2015

    • Author(s)
      Izumi K, Mine K, Inoue Y, Teshima M, Ogawa S, Kai Y, Kurafuji T, Hirakawa K, Miyakawa D, Ikeda H, Inada A, Hara M, Yamada H, Akashi K, Niho Y, Ina K, Kobayashi T, Yoshikai Y, Anzai K, Yamashita T, Minagawa H, Fujimoto S, Kurisaki H, Shimoda K, Katsuta H, Nagafuchi S.
    • Journal Title

      Nat Commun.

      Volume: 6 Issue: 1 Pages: 1-10

    • DOI

      10.1038/ncomms7748

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis.2015

    • Author(s)
      Ayano M, Tsukamoto H, Kohno K, et al.
    • Journal Title

      J Immunol

      Volume: 195 Issue: 3 Pages: 892-900

    • DOI

      10.4049/jimmunol.1403046

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma.2015

    • Author(s)
      Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, Sugita Y, Yufu Y, Choi I, Abe Y, Uike N, Nagafuji K, Okamura T, Akashi K, Takayanagi R, Shiratsuchi M, Ohshima K.
    • Journal Title

      Blood

      Volume: 126 Issue: 19 Pages: 2193-2201

    • DOI

      10.1182/blood-2015-02-629600

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Natural killer cells regulate T cell immune responses in primary biliary cirrhosis.2015

    • Author(s)
      Shimoda S, Hisamoto S, Harada K, Iwasaka S, Chong Y, Nakamura M, Bekki Y, Yoshizumi T, Shirabe K, Ikegami T, Maehara Y, He XS, Gershwin ME, Akashi K.
    • Journal Title

      Hepatology.

      Volume: 62 Issue: 6 Pages: 1817-1827

    • DOI

      10.1002/hep.28122

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression.2015

    • Author(s)
      Kikushige Y, Miyamoto T, Yuda J, Jabbarzadeh-Tabrizi S, Shima T, Takayanagi S, Niiro H, Yurino A, Miyawaki K, Takenaka K, Iwasaki H, Akashi K
    • Journal Title

      Cell Stem Cell.

      Volume: 17 Issue: 3 Pages: 341-352

    • DOI

      10.1016/j.stem.2015.07.011

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice.2015

    • Author(s)
      Uryu H, Hashimoto D, Kato K, Hayase E, Matsuoka S, Ogasawara R, Takahashi S, Maeda Y, Iwasaki H, Miyamoto T, Saijo S, Iwakura Y, Hill GR, Akashi K, Teshima T.:
    • Journal Title

      Blood

      Volume: 125 Issue: 19 Pages: 3014-23

    • DOI

      10.1182/blood-2014-12-615781

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis: redefinition of murine common myeloid progenitor.2015

    • Author(s)
      Miyawaki K, Arinobu Y, Iwasaki H, Kohno K, Tsuzuki H, Iino T, Shima T, Kikushige Y, Takenaka K, Miyamoto T, Akashi K.
    • Journal Title

      Stem Cells

      Volume: 33 Issue: 3 Pages: 976-87

    • DOI

      10.1002/stem.1906

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria.2014

    • Author(s)
      Yonekawa A, Saijo S, Hoshino Y, Miyake Y, Ishikawa E, Suzukawa M, Inoue H, Tanaka M, Yoneyama M, Oh-Hora M, Akashi K, Yamasaki S.
    • Journal Title

      Immunity

      Volume: 41 Issue: 3 Pages: 402-13

    • DOI

      10.1016/j.immuni.2014.08.005

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation.2014

    • Author(s)
      Nobusue H
    • Journal Title

      Nat Commun

      Volume: 5 Issue: 1 Pages: 3368-3368

    • DOI

      10.1038/ncomms4368

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell.2014

    • Author(s)
      Shima T, Miyamoto T, Kikushige Y, Yuda J, Tochigi T, Yoshimoto G, Kato K, Takenaka K, Iwasaki H, Mizuno S, Goto N, Akashi K.
    • Journal Title

      Exp. Hematol.

      Volume: 42 Issue: 11 Pages: 955-65

    • DOI

      10.1016/j.exphem.2014.07.267

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical impact of fluoroquinolone-resistant Escherichia coli in the fecal flora of hematological patients with neutropenia and levofloxacin prophylaxis.2014

    • Author(s)
      Chong Y, Shimoda S, Yakushiji H, Ito Y, Aoki T, Miyamoto T, Kamimura T, Shimono N, Akashi K.
    • Journal Title

      PLoS One

      Volume: 9 Issue: 1 Pages: e85210-e85210

    • DOI

      10.1371/journal.pone.0085210

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment.2014

    • Author(s)
      Iwamoto C
    • Journal Title

      Exp Hematol

      Volume: 42 Issue: 3 Pages: 163-171

    • DOI

      10.1016/j.exphem.2013.11.005

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Clinical aspects of primary myelofibrosis in Japan.2014

    • Author(s)
      Shimoda K
    • Journal Title

      臨床血液

      Volume: 55 Pages: 289-294

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment.2013

    • Author(s)
      Yamauchi T
    • Journal Title

      Blood

      Volume: 121 Issue: 8 Pages: 1316-1325

    • DOI

      10.1182/blood-2012-06-440354

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] TIM-3 and its ligand, galectin-9, constitute an autocrine loop critical for development of human myeloid leukemia stem cells2016

    • Author(s)
      Koichi Akashi
    • Organizer
      JSPS-NUS Joint Symposium“New Horizons in Normal and Cancer Stem Cell Research”
    • Place of Presentation
      Singapore
    • Year and Date
      2016-01-14
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] TIM-3 and its ligand, galectin-9 constitute an autocrine loop to maintain stem cells in most human myeloid malignancies.2015

    • Author(s)
      Koichi Akashi
    • Organizer
      2015 ISEH Annual Meeting
    • Place of Presentation
      Kyoto
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 骨髄系白血病幹細胞における共通の鍵分子TIM-3とその臨床応用2015

    • Author(s)
      赤司 浩一
    • Organizer
      第39回阿蘇シンポジウム
    • Place of Presentation
      阿蘇
    • Year and Date
      2015-08-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] TIM-3 Signaling and Human Myeloid Leukemia Stem Cell Development2015

    • Author(s)
      Koichi Akashi
    • Organizer
      KEYSTONE SYMPOSIA
    • Place of Presentation
      Keystone, Colorado USA
    • Year and Date
      2015-02-26
    • Related Report
      2014 Annual Research Report
  • [Presentation] 白血病幹細胞研究のすゝめ2014

    • Author(s)
      赤司 浩一
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2014-11-02
    • Related Report
      2014 Annual Research Report
  • [Presentation] 造血器腫瘍幹細胞2014

    • Author(s)
      赤司 浩一
    • Organizer
      第101回近畿血液学地方会
    • Place of Presentation
      大阪
    • Year and Date
      2014-06-28
    • Related Report
      2014 Annual Research Report
  • [Presentation] TIM-3, as a Target for Eradication of Cancer Stem Cells2014

    • Author(s)
      Koichi Akashi
    • Organizer
      The Uehara Memorial Foundation Symposium
    • Place of Presentation
      東京
    • Year and Date
      2014-06-17
    • Related Report
      2014 Annual Research Report
  • [Presentation] 造血器腫瘍幹細胞2014

    • Author(s)
      赤司 浩一
    • Organizer
      第3回日本血液学会東海地方会
    • Place of Presentation
      名古屋
    • Year and Date
      2014-04-26
    • Related Report
      2014 Annual Research Report
  • [Presentation] Cancer Stem Cell2014

    • Author(s)
      赤司 浩一
    • Organizer
      第87回日本内分泌学会学術総会
    • Place of Presentation
      福岡
    • Year and Date
      2014-04-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] 造血幹細胞と造血器癌幹細胞

    • Author(s)
      赤司浩一
    • Organizer
      第110回日本内科学会
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Epigenetic landscape of hematopoiesis visualized by histone H3.3 incorporation is deregulated in acute myeloid leukemia

    • Author(s)
      Koichi Akashi
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Cancer Stem Cells in Human Hematological Malignancies

    • Author(s)
      Koichi Akashi
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 造血器癌幹細胞  Malignant hematopoietic stem cell

    • Author(s)
      赤司浩一
    • Organizer
      第55回日本小児血液・がん学会学術集会
    • Place of Presentation
      福岡
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 治療標的としてのヒト白血病幹細胞

    • Author(s)
      赤司浩一
    • Organizer
      「がん研究分野の特性等を踏まえた支援活動」公開シンポジウム
    • Place of Presentation
      東京
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Remarks] 九州大学医学部第一内科(病態修復内科)

    • URL

      http://www.1nai.med.kyushu-u.ac.jp

    • Related Report
      2014 Annual Research Report
  • [Remarks] 九州大学医学部第一内科

    • URL

      http://www.1nai.med.kyushu-u.ac.jp

    • Related Report
      2013 Annual Research Report
  • [Remarks] 新学術領域研究「癌幹細胞を標的とする腫瘍根絶技術の新構築」

    • URL

      http://www.cancer-stem-cell.com

    • Related Report
      2013 Annual Research Report

URL: 

Published: 2013-05-15   Modified: 2019-07-29  

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