Cancer stem cell assay by a new immunodeficient mouse model Cancer stem cell assay by a new immunodeficient mouse model harboring with optimal bone marrow microenvironment

• Project/Area Number: 15K15365
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: Akashi Koichi 九州大学, 医学研究院, 教授 (80380385)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: がん幹細胞 / 異種移植アッセイ / 免疫不全マウス / マクロファージ / SIRPA / 骨髄ニッチ / ヒト疾患モデル / マクロファージ寛容 / 幹細胞アッセイシステム / 異種移植モデル

Outline of Final Research Achievements

To evaluate human cancer stem cells in xenotransplantation models, a variety of immunodeficient mouse lines have been developed. We found that in xenograft engraftment, inhibition of phagocytic reaction of mouse macrophages is essential in addition to lymphoid depletion. Here, we have established a new immunodeficient BRGhS mouse line, harbouring a complete macrophage tolerance. Furthermore, we introduced KITW/v mutation into BRGhS line to optimize mouse bone marrow microenvironment for human cell engraftment. This strain should be very useful for human cancer stem cell assay.

Research Products

• [Journal Article] Identification of unipotent megakaryocyte progenitors in human hematopoiesis. (2017)
  • Author(s): K. Miyawaki. Iwasaki, T. Jiromaru, H. Kusumoto, A. Yurino, T. Sugio, Y. Uehara, J. Odawara, S. Daitoku, Y. Kunisaki, Y. Mori, Y. Arinobu, H. Tsuzuki, Y. Kikushige, T. Iino, K. Kato, K. Takenaka, T. Miyamoto, T. Maeda, *K. Akashi
  • Journal Title: Blood Volume: 印刷中 Issue: 25 Pages: 3332-3343
  • DOI: 10.1182/blood-2016-09-741611
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Notch1 expression is regulated at the post-transcriptional level by the 3′ untranslated region in hematopoietic stem cell development (2017)
  • Author(s): Mizuno Shinichi、Iino Tadafumi、Ozawa Hidetoshi、Arinobu Yojiro、Chong Yong、Akashi Koichi
  • Journal Title: International Journal of Hematology Volume: 107 Issue: 3 Pages: 311-319
  • DOI: 10.1007/s12185-017-2358-2
  • Peer Reviewed / Open Access
• [Journal Article] Persistent detection of alternatively spliced BCR-ABL variant results in a failure to achieve deep molecular response (2017)
  • Author(s): Yuda Junichiro、Miyamoto Toshihiro、Odawara Jun、Ohkawa Yasuyuki、Semba Yuichiro、Hayashi Masayasu、Miyamura Koichi、Tanimoto Mitsune、Yamamoto Kazuhito、Taniwaki Masafumi、Akashi Koichi
  • Journal Title: Cancer Science Volume: 108 Issue: 11 Pages: 2204-2212
  • DOI: 10.1111/cas.13353
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a human clonogenic progenitor with strict monocyte differentiation potential: A counterpart of mouse cMoPs (2017)
  • Author(s): Kawamura S, Onai N, Miya F, Sato T, Tsunoda T, Kurabayashi K, Yotsumoto S, Kuroda S, Takenaka K, Akashi K, Ohteki T
  • Journal Title: Immunity Volume: 46 Issue: 5 Pages: 835-848
  • DOI: 10.1016/j.immuni.2017.04.019
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical features and outcomes of patients with primary myelofibrosis in Japan: report of a 17-year nationwide survey by the Idiopathic Disorders of Hematopoietic Organs Research Committee of Japan. (2017)
  • Author(s): Takenaka K, Shimoda K, Uchida N, Shimomura T, Nagafuji K, Kondo T, Shibayama H, Mori T, Usuki K, Azuma T, Tsutsumi Y, Tanaka J, Dairaku H, Matsuo K, Ozawa K, Kurokawa M, Arai S, Akashi K.
  • Journal Title: Int J Henatol Volume: 105 Issue: 1 Pages: 59-69
  • DOI: 10.1007/s12185-016-2102-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Functional interleukin-33 receptors are expressed in early progenitor stages of allergy-related granulocytes. (2017)
  • Author(s): Tsuzuki H, Arinobu Y, Miyawaki K, Takaki A, Ota SI, Ota Y, Mitoma H, Akahoshi M, Mori Y, Iwasaki H, Niiro H, Tsukamoto H, and Akashi K.
  • Journal Title: Immunology Volume: 150 Issue: 1 Pages: 64-73
  • DOI: 10.1111/imm.12667
  • Peer Reviewed / Open Access
• [Journal Article] Calreticulin mutation does not contribute to disease progression in essential thrombocythemia by inhibiting phagocytosis. (2016)
  • Author(s): S. Daitoku, K. Takenaka, T. Yamauchi, A. Yurino, F. Jinnouchi, T. Nunomura, T. Eto, T. Kamimura, M. Higuchi, N. Harada, N. Saito, T. Miyamoto, H. Iwasaki, *K. Akashi
  • Journal Title: Exp Hematol Volume: 44 Issue: 9 Pages: 817-825
  • DOI: 10.1016/j.exphem.2016.05.001
  • Peer Reviewed
• [Journal Article] Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations. (2016)
  • Author(s): A. Yurino, K. Takenaka, T. Yamauchi, T. Nunomura, Y. Uehara, F. Jinnouchi, K. Miyawaki, Y. Kikushige, K. Kato, T. Miyamoto, H. Iwasaki, Y. Kunisaki, *K. Akashi
  • Journal Title: Stem Cell Reports Volume: 7 Issue: 3 Pages: 425-438
  • DOI: 10.1016/j.stemcr.2016.07.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficacy and safety analysis of chemotherapy for advanced colitis-associated colorectal cancer in Japan. (2016)
  • Author(s): Nio K, Higashi D, Kumagai H, Arita S, Shirakawa T, Nakashima K, Shibata Y, Esaki M, Manabe T, Nagai S, Ueki T, Nakano M, Ariyama H, Kusaba H, Hirahashi M, Oda Y, Esaki T, Mitsugi K, Futami K, Akashi K, Baba E.
  • Journal Title: Anticancer Drugs Volume: 27 Issue: 5 Pages: 457-463
  • DOI: 10.1097/cad.0000000000000338
  • Peer Reviewed
• [Journal Article] Reduced Dose of Salvage-line Regorafenib Monotherapy for Metastatic Colorectal Cancer in Japan. (2015)
  • Author(s): Hirano G, Makiyama A, Makiyama C, Esaki T, Oda H, Uchino K, Komoda M, Tanaka R, Matsushita Y, Mitsugi K, Shibata Y, Kumagai H, Arita S, Ariyama H, Kusaba H, Akashi K, Baba E.
  • Journal Title: Anticancer Res Volume: 35 Pages: 371-377
  • Peer Reviewed
• [Journal Article] Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T-cell leukemia/lymphoma in a pilot study. (2015)
  • Author(s): Suehiro Y, Atsuhiko Hasegawa A, Tadafumi Iino T, Amane Sasada A, Nobukazu Watanabe N, Masao Matsuoka M, Ayako Takamori A, Ryuji Tanosaki R, Atae Utsunomiya A, Ilseung Choi I, Tetsuya Fukuda T, Osamu Miura O, Shigeo Takaishi S, Takanori Teshima T, Koichi Akashi K, Mari Kannagi M, Naokuni Uike N, Jun Okamura J
  • Journal Title: Br J Haematol Volume: 169 Issue: 3 Pages: 356-367
  • DOI: 10.1111/bjh.13302
  • Peer Reviewed
• [Journal Article] A multinational, open-label, phase 2 study of ruxolitinib in Asian patients with myelofibrosis: Japanese subset analysis. (2015)
  • Author(s): Oritani K, Okamoto S, Tauchi T, Saito S, Ohishi K, Handa H, Takenaka K, Gopalakrishna P, Amagasaki T, Ito K, Akashi K.
  • Journal Title: Int J Hematol Volume: 101 Issue: 3 Pages: 295-304
  • DOI: 10.1007/s12185-015-1746-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Factors prognostic of eligibility for allogeneic HCT among older patients with AML-CR1 and adverse- or intermediate-risk cytogenetics. (2015)
  • Author(s): Yamasaki S, Yoshimoto G, Ogawa R, Aoki K, Higuchi M, Harada N, Arima F, Kondo S, Matubara F, Takahashi T, Uike N, Miyamoto T, Okamura S, Akashi K.
  • Journal Title: Ann Hematol Volume: 94 Issue: 7 Pages: 1159-1165
  • DOI: 10.1007/s00277-015-2338-7
  • Peer Reviewed
• [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] 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] HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide after Busulfan-Containing Reduced-Intensity Conditioning. (2015)
  • Author(s): Sugita J, Kawashima N, Fujisaki T, Kakihana K, Ota S, Matsuo K, Miyamoto T, Akashi K, Taniguchi S, Harada M, Teshima T.
  • Journal Title: Biol Blood Marrow Transplant Volume: 21 Issue: 9 Pages: 1646-1652
  • DOI: 10.1016/j.bbmt.2015.06.008
  • Peer Reviewed
• [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] 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] Chd5 Regulates MuERV-L/MERVL Expression in Mouse Embryonic Stem Cells Via H3K27me3 Modification and Histone H3.1/H3.2. (2015)
  • Author(s): Hayashi M, Maehara K, Harada A, Semba Y, Kudo K, Takahashi H, Oki S, Meno C, Ichiyanagi K, Akashi K, Ohkawa Y.
  • Journal Title: J Cell Biochem Volume: 117 Issue: 3 Pages: 780-792
  • DOI: 10.1002/jcb.25368
  • Peer Reviewed / Open Access
• [Journal Article] Splenic irradiation provides transient palliation for symptomatic splenomegaly associated with primary myelofibrosis: a report on 14 patients. (2015)
  • Author(s): Kitanaka A, Takenaka K, Shide K, Miyamoto T, Kondo T, Ozawa K, Kurokawa M, Akashi K, Shimoda K.
  • Journal Title: Int J Hematol Volume: 103 Issue: 4 Pages: 423-428
  • DOI: 10.1007/s12185-016-1940-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] がん幹細胞研究の進歩と治療開発 (2017)
  • Author(s): 赤司浩一
  • Organizer: 第114回日本内科学会総会・講演会
  • Invited
• [Presentation] 骨髄性白血病幹細胞成立におけるTIM-3/Gal-9オートクラインシグナルの役割 (2017)
  • Author(s): 赤司浩一
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] ヒト白血病幹細胞研究の進歩 (2017)
  • Author(s): 赤司浩一
  • Organizer: 第54回日本臨床分子医学会学術集会
  • Invited
• [Presentation] ヒト骨髄性白血病に共通する悪性幹細胞の自己再生メカニズム (2016)
  • Author(s): 赤司 浩一
  • Organizer: The 47th International Symposium of the Princess Takamatsu Cancer Research Fund
  • Place of Presentation: 東京
  • Year and Date: 2016-11-08
  • Invited
• [Presentation] TIM-3/Galectin-9 axis is a potential therapeutic target for human myeloid leukemia stem cells (2016)
  • Author(s): 赤司 浩一
  • Organizer: 第14回日本臨床腫瘍学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2016-07-29
  • Invited
• [Presentation] TIM-3 and Its Ligand, Galectin-9, Constitute an Autocrine Loop Universally Critical for Development of Human Myeloid Leukemia Stem Cells (2016)
  • Author(s): Koichi Akashi
  • Organizer: JCA-AACR Special Joint Conference
  • Place of Presentation: 東京
  • Year and Date: 2016-07-14
  • Int'l Joint Research / Invited
• [Presentation] A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of hu- man myeloid leukemia stem cells and leukemic progression (2016)
  • Author(s): Koichi Akashi
  • Organizer: THE 41st 1NAITO CONFERENCE
  • Place of Presentation: 札幌
  • Year and Date: 2016-07-06
  • Invited
• [Presentation] ヒト白血病幹細胞研究の進歩 (2016)
  • Author(s): 赤司 浩一
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府
  • Year and Date: 2016-05-31
  • Invited
• [Presentation] ヒト白血病幹細胞研究の進歩 (2016)
  • Author(s): 赤司 浩一
  • Organizer: 第51回日本血液学会春季北海道地方会
  • Place of Presentation: 札幌
  • Year and Date: 2016-04-09
  • Invited
• [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 / Invited
• [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 Japan
  • Year and Date: 2015-09-17
  • Int'l Joint Research / Invited