Centers & Labs

RIKEN Center for Integrative Medical Sciences

Laboratory for Human Disease Models

Group Director: Fumihiko Ishikawa (M.D., Ph.D)
Fumihiko  Ishikawa(M.D., Ph.D)

We have developed the immunologically-humanized mouse by transplanting prospectively isolated human cord blood hematopoietic stem cells into the newborn NOD/SCID/IL2Rg-null (NSG) mice. Humanized NSG mice enable us to investigate in vivo dynamics of human immunity. Furthermore, we aim to generate novel strains of immune-compromised mice with humanized microenvironment to analyze interaction of various immune subsets or that between human immunity and diseases.

We have also succeeded in recapitulating human leukemia in NOD/SCID/IL2Rg null mice. By using the leukemic xenograft model, we found that CD34+CD38- AML stem cells are resistant to conventional chemotherapy through cell cycle quiescence at bone marrow niche. We are currently trying to create novel therapeutic strategies targeting AML stem cells. In particular, we found several potential therapeutic molecules that are highly over-represented in AML stem cells not in normal hematopoietic stem cells. We hope to develop anti-LSC therapies targeting these specific molecules.

Main Research Field

Medicine, dentistry, and pharmacy

Related Research Fields

Biological Sciences

Research Subjects

  • Understanding human hematopoiesis & immunity using humanized mouse
  • Identification of cancer stem cells
  • Development of humanized mouse models for primary immunodeficiency diseases

Selected Publications

  1. Najima Y, Tomizawa- Murasawa M, Saito Y, Watanabe T, Ono R, Ochi T, Suzuki N, Fujiwara H, Ohara O, Shultz LD, Yasukawa M, Ishikawa F.:
    "Induction of WT1-specific human CD8+ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice"
    Blood 127 , 722-34, 2016
  2. Aoki Y, Watanabe T, Saito Y, Kuroki Y, Hijikata A, Takagi M, Tomizawa D, Eguchi M, Eguchi-Ishimae M, Kaneko A, Ono R, Sato K, Suzuki N, Fujiki S, Koh K, Ishii E, Shultz LD, OharaO, Mizutani S, Ishikawa F.:
    "Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia"
    Blood 125, 967-80, 2015.
  3. Saito Y, Yuki H, Kuratani M, Hashizume Y, Takagi S, Honma T, Tanaka A, Shirouzu M, Mikuni J, Handa N, Ogahara I, Sone A, Najima Y, Tomabechi Y, Wakiyama M, Uchida N, Tomizawa-Murasawa M, Kaneko A, Tanaka S, Suzuki N, Kajita H, Aoki Y, Ohara O, Shultz LD, Fukami T, Goto T, Taniguchi S, Yokoyama S and Ishikawa F.:
    "A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivor"
    Sci Transl Med 5, 181ra52, 2013.
  4. Takagi S, Saito Y, Hijikata A, Tanaka S, Watanabe T, Hasegawa T, Mochizuki S, Kunisawa J, Kiyono H, Koseki H, Ohara O, Saito T, Taniguchi S, Shultz LD, Ishikawa F.:
    "Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation."
    Blood 119, 2768-2777, 2012.
  5. Tanaka S, Saito Y, Kunisawa J, Kurashima Y, Wake T, Sazuki N, Shultz LD, Kiyono H, Ishikawa F.:
    "Development of mature and functional human myeloid subsets in hematopoietic stem cell-engrafted NOD/SCID/IL2rγKO mice"
    J Immunol 188, 6145-55, 2012.
  6. Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa-Murasawa M, Doi T, Sone A, Suzuki N, Fujiwara H, Yasukawa M, Ishikawa F.:
    "Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I exprtessing NOD/SCID/IL2rγnull humanized mice."
    Proc Natl Acad of Sci U S A 107, 13022-7, 2010.
  7. Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A, Najima Y, Takagi S, Aoki Y, Wake A, Taniguchi S, Shultz LD, Ishikawa F.:
    "Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML"
    Nat Biotechnol 28, 275-80, 2010.
  8. Saito Y, KitamuraH, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S, Uchida N, Suzuki N, Sone A, Najima Y, Ozawa H, Wake A, Taniguchi S, Shultz LD, Ohara O, Ishikawa F.:
    "Identification for therapeutic targets for quiescent chemotherapy-resistant human AML stem cells"
    Sci Transl Med 2, 17ra9, 2010.
  9. Ishikawa F, Yoshika S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD.:
    "Chemotherapy-resistant human AML stem cells home to and engraft within the bone marrow endosteal region"
    Nat Biotechnol 25, 1315-21, 2007.
  10. Shultz LD, Ishikawa F, Greiner DL.:
    "Humanized mice in translational biomedical research"
    Nat Rev Immunol 7, 118-30, 2007.

Lab Members

Principal Investigator

Fumihiko Ishikawa
Group Director

Core Members

Yoriko Saito
Senior Research Scientist
Rintaro Ono
Junior Research Associate
Kaori Sato
Technical Staff I
Ikuko Ogahara
Technical Staff I
Hiroshi Kajita
Technical Staff II
Nahoko Suzuki
Technical Staff II
Saera Fujiki
Technical Staff II
Akiko Kaneko
Technical Staff II

Contact information

1-7-22 Suehiro-cho, Tsurumi-ku,
Yokohama City, Kanagawa,
230-0045, Japan
Tel: +81-(0)45-503-9448
Fax: +81-(0)45-503-7068

Email: fumihiko.ishikawa [at] riken.jp

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