Laboratory for Human Disease Model

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.

Research Fields

Immunology

Research Subjects

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

Publications

1. 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"
   Science Translational Medicine 5-181: 181ra52, 2013.
   
2. 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.
   
3. 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."
   Proceedings of the National Academy of Science of the United States of America 107-29:13022-13027, 2010.
   
4. 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.:
   "Cell cycle entry potentiates elimination of quiescent chemotherapy-resistant human AML stem cells."
   Nature Biotechnology 28-3:275-280, 2010.
   
5. 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"
   Science Translational Medicine 2-17: 17 ra 9, 2010.
   
6. Ishikawa F, Saito Y, Shultz LD.:
   "Modeling human leukemia using immune-compromised mice. In "Mouse Models of Human Blood Cancer:Basic Research and Pre-Clinical Applications(Li,S,Editor)""
   Springer Science+Business Media, LLC, New York, 2008.
   
7. Saito Y and Ishikawa F.:
   "The Origin of Blood: Induction of hematopoietic stem cells from different sources."
   Cell Stem Cell: 8-10, 2008.
   
8. 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."
   Nature Biotechnol 25: 1315-1321, 2007.
   
9. Ishikawa F, Niiro H, Iino T, Yoshida S, Saito N, Onohara S, Miyamoto T, Miyagawa H, Fujii SI, Shultz LD, Harada M, Akashi K.:
   "The developmental program of human dendritic cells is operated indeoendently of conventional myeloid and lymphoid pathways."
   Blood 119: 3591-3660, 2007.
   
10. Shultz LD, Ishikawa F, Greiner DL.:
    "Humanized mice in translational biomedical research"
    Nature Reviews Immunol , 7:118-130,2007.