Establishment of the myeloid leukemic stem cell-targeted therapy

• Project/Area Number: 25253069
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyushu 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: ¥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.

Research Products

• [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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Presentation] TIM-3 and its ligand, galectin-9, constitute an autocrine loop critical for development of human myeloid leukemia stem cells (2016)
  • 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
  • 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
  • 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
• [Presentation] TIM-3 Signaling and Human Myeloid Leukemia Stem Cell Development (2015)
  • Author(s): Koichi Akashi
  • Organizer: KEYSTONE SYMPOSIA
  • Place of Presentation: Keystone, Colorado USA
  • Year and Date: 2015-02-26
• [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
• [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
• [Presentation] TIM-3, as a Target for Eradication of Cancer Stem Cells (2014)
  • Author(s): Koichi Akashi
  • Organizer: The Uehara Memorial Foundation Symposium
  • Place of Presentation: 東京
  • Year and Date: 2014-06-17
• [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
• [Presentation] Cancer Stem Cell (2014)
  • 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
• [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
  • 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
  • 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
  • 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
  • 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
  • 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
• [Remarks] 九州大学医学部第一内科
  • URL: http://www.1nai.med.kyushu-u.ac.jp
• [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