Development of a novel human leukemia model using humanized mice

• Project/Area Number: 24659487
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: ISHII Naoto 東北大学, 医学(系)研究科(研究院), 教授 (60291267)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 白血病 / ヒト化マウス / 動物モデル / 白血病モデル / MLLキメラ遺伝子

Research Abstract

In vivo studies in which primary human leukemia cells were transplanted into immunodeficient mice, provided significant advances in our understanding of the pathogenesis of human leukemia. However, these models, in which the leukemia cells had already developed in human patients before being transplanted into mice, are not suitable for studying physiological leukemogenesis. Therefore, we here developed a new experimental model for analyzing leukemogenesis in which primary human HSCs are converted into leukemia cells by deliberate genetic hits. We hope that this newly established model using humanized mice will contribute to future studies aimed at revealing the molecular mechanisms for leukemogenesis and developing new therapies against leukemia.

Research Products

• [Journal Article] TNF receptor-associated factor 5 limits inflammatory CD4^+ T cell differentiation by antagonizing IL-6-receptor signaling (2014)
  • Author(s): Nagashima H, Okuyama Y, Asao A, Kawabe T, Yamaki S, Nakano H, Croft M, Ishii N, and So T
  • Journal Title: Nat. Immunol. Volume: 15 Pages: 449-456
  • DOI: 10.1038/ni.2863
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Activation of Notch1 promotes development of human CD8^+ single positive T cells in humanized mice (2014)
  • Author(s): Haji Y, Suzuki M, Moriya K, So T, Hozumi K, Mizuma M, Unno M, and Ishii N.
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 447 Pages: 346-351
  • DOI: 10.1016/j.bbrc.2014.04.003
  • Peer Reviewed
• [Journal Article] OX40 ligand regulates splenic CD8(-) dendritic cell-induced Th2 responses in vivo. (2014)
  • Author(s): Kamachi F, Harada N, Usui Y, Sakanishi T, Ishii N, Okumura K, Miyake S, Akiba H
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 444 Pages: 235-240
  • DOI: 10.1016/j.bbrc.2014.01.060
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells (2014)
  • Author(s): Nagata T, Murata K, Murata R, Sun S-L, Saito Y, Yamaga S, Tanaka N, Tamai K, Moriya K, Kasai N, Sugamura K, and Ishii N.
  • Journal Title: Biochem Biophys Res Commun. Volume: 443 Pages: 351-356
  • DOI: 10.1016/j.bbrc.2013.11.029
  • Peer Reviewed
• [Journal Article] Activation of Notch1 promotes development of human CD8+ single positive T cells in humanized mice (2014)
  • Author(s): Haji Y, Suzuki M, Moriya K, So T, Hozumi K, Mizuma M, Unno M, and Ishii N
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector. (2013)
  • Author(s): Horino S, Uchiyama T, So T, Nagashima H, Sun SL, Sato M, Asao A, Haji Y, Sasahara Y, Candotti F, Tsuchiya S, Kure S, Sugamura K, and Ishii N
  • Journal Title: PLos One Volume: 8
  • DOI: 10.1371/journal.pone.0071594
  • Peer Reviewed
• [Journal Article] Y chromosome-linked B and NK cell deficiency in mice. (2013)
  • Author(s): Sun SL, Horino S, Itoh-Nakadai A, Kawabe T, Asao A, Takahashi T, So T, Funayama R, Kondo M, Saitsu H, Matumoto N, Nakayama K, and Ishii N
  • Journal Title: J. Immunol Volume: 190 Pages: 6209-6220
  • DOI: 10.4049/jimmunol.1300303
  • Peer Reviewed
• [Journal Article] Homeostatic proliferation of naïve CD4^+ T cells in mesenteric lymph nodes generates gut-tropic Th17 cells (2013)
  • Author(s): Kawabe T, Sun SL, Fujita T, Yamaki S, Asao A, Takahashi T, So T, Ishii N
  • Journal Title: J. Immunol Volume: 190 Pages: 15788-5798
  • DOI: 10.4049/jimmunol.1203111
  • Peer Reviewed
• [Journal Article] A small molecule inhibitor to plasminogen activator inhibitor l inhibits macrophage migration. (2013)
  • Author(s): Ichimura A, Matsumoto S, Suzuki S, Dan T, Yamaki S, Sato Y, Kiyomoto H, Ishii N, Okada K, Matsuo O, Hou FF, Vaughan DE, van Ypersele de Strihou S, Miyata T.
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. Volume: 33 Pages: 935-42
  • DOI: 10.1161/atvbaha.113.301224
  • Peer Reviewed
• [Journal Article] Potential utility of eGFP-expressing NOG mice (NOG-EGFP) as a high purity cancer sampling system. (2012)
  • Author(s): Shima K, et al
  • Journal Title: J. Exp Clin Cancer Res Volume: 31 Pages: 33-33
  • DOI: 10.1186/1756-9966-31-55
  • URL: http://www.jeccr.com/content/31/1/55
  • Peer Reviewed
• [Journal Article] Development of a multi-step leukemogenesis model of MLL-rearranged leukemia using humanized mice. (2012)
  • Author(s): Moriya K, Suzuki M, Watanabe Y, Takahashi T, Aoki Y, Uchiyama T, Kumaki S, Sasahara Y, Minegishi M, Kure S, Tsuchiya S, Sugamura K, and Ishii N.
  • Journal Title: PLoS One Volume: 7(6)
  • DOI: 10.1371/journal.pone.0037892
  • Peer Reviewed
• [Journal Article] Runx1-deficiency in CD4^+ T cells causes fatal autoimmune inflammatory lung disease due to spontaneous hyperactivation of cells (2012)
  • Author(s): Wong WF, Tazawa R, （15名略）Nakata K, Takai T, Satake M.
  • Journal Title: J. Immunol Volume: 188(11) Pages: 5408-20
  • DOI: 10.4049/jimmunol.1102991
  • Peer Reviewed
• [Journal Article] Induction of human humoral immune responses in a novel HLA-DR-expressing transgenic NOD/Shi-scid/γcnull mouse. (2012)
  • Author(s): Suzuki M, Takahashi T, Katano I, Ito R, Ito M, Harigae H, Ishii N, Sugamura K.
  • Journal Title: Int. Immunol Volume: 24 Pages: 208-214
  • DOI: 10.1093/intimm/dxs045
  • Peer Reviewed
• [Presentation] Th17 cell generation and mucosal immunity (2013)
  • Author(s): Takeshi Kawabe, Shu-lan Sun, Satoshi Yamaki, Atsuko Asao, Takeshi Takahashi, Takanori So, and Naoto Ishii
  • Organizer: Annual International Symposium of Rheumatology Institute of Seoul National University Hospital
  • Place of Presentation: Seoul
  • Year and Date: 2013-06-28
• [Presentation] Homeostatic proliferation of naïve CD4 T cells in mesenteric lymph nodes generates gut-tropic Th17 cells (2013)
  • Author(s): Takeshi Kawabe, Shu-lan Sun, Satoshi Yamaki, Atsuko Asao, Takeshi Takahashi, Takanori So, and Naoto Ishii
  • Organizer: The 1st Symposium of International Immunological Memory and Vaccine Forum
  • Place of Presentation: 東京
  • Year and Date: 2013-01-29
• [Presentation] Y chromosome-linked B and NK cell deficiency in mice (2013)
  • Author(s): Sun SL, Itoh A, Asao A, Takahashi T, So T, Kondo M, Ishii N.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 千葉市
• [Presentation] TRAF5 controls inflammatory CD4 T cells in experimental autoimmune encephalomyelitis (2013)
  • Author(s): Nagashima H, Yamaki S, Asao A, Croft M, Ishii N, So T.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 千葉市
• [Presentation] 腸管Th17細胞の産生における腸間膜リンパ節の役割 (2013)
  • Author(s): 河部剛史、孫舒嵐、鈴木信、山木聡史、浅尾敦子、宗孝紀、石井直人
  • Organizer: 第67回日本細菌学会東北支部総会
  • Place of Presentation: 仙台市
• [Presentation] TRAF5欠損マウスでは実験的自己免疫性脳脊髄炎が増悪する (2013)
  • Author(s): 長島宏行、山木聡史、浅尾敦子、Michael Croft、石井直人、宗孝紀
  • Organizer: 第67回日本細菌学会東北支部総会
  • Place of Presentation: 仙台市
• [Presentation] Y-Chromosome-linked B- and NK-cell deficiency in mice (2013)
  • Author(s): Shu-lan Sun, Satoshi Horino, Ari Ito, Takeshi Kawabe, Atsuko Asao, Takeshi Takahashi, Takanori So, Motonari Kondo, and Naoto Ishii
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milano, Italy
• [Presentation] Homeostatic proliferation of naïve CD4 T cells in mesenteric lymph nodes generates gut-tropic Th17 cells (2013)
  • Author(s): Takeshi Kawabe, Shu-lan Sun, Satoshi Yamaki, Atsuko Asao, Takeshi Takahashi, Takanori So, and Naoto Ishii
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milano, Italy
• [Presentation] Homeostatic proliferation of naïve CD4 T cells in mesenteric lymph nodes generates gut-tropic Th17 cells (2013)
  • Author(s): Takeshi Kawabe, Shu-lan Sun, Satoshi Yamaki, Atsuko Asao, Takeshi Takahashi, Takanori So, and Naoto Ishii
  • Organizer: NIH-Tohoku University-JSPS Symposium
  • Place of Presentation: Sendai
• [Presentation] Homeostatic proliferation occurs in mesenteric lymph nodes generates gut-tropic Th17 cells. (2013)
  • Author(s): Takeshi Kawabe et al.
  • Organizer: The 1st Symposium of International Immunological Memory and Vaccine Forum
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] TNF receptor-associated factor 5 inhibits Th17 and Tfh differentiation (2012)
  • Author(s): Nagashima H, Yamaki S, Croft M, Ishii N, So T.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸市
• [Presentation] Homeostatic proliferation occurs in mesenteric lymph nodes and supplies effector memory CD4^+ T cells in the intestine (2012)
  • Author(s): Kawabe T, Sun SL, Yamaki S, Asao A, Takahashi T, So T, Ishii N.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸市
• [Presentation] L-arginine upregulates NO production by macrophages during infection with Leishmania major (2012)
  • Author(s): Asao A, So T, Hoshino T, Asao H, Sugmura K, Ishii N.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸市
• [Presentation] リーシュマニア原虫感染防御におけるL-アルギニンの効果 (2012)
  • Author(s): 浅尾敦子、宗孝紀、Lishomwa C. Ndhlovu、浅尾裕信、菅村和夫、石井直人
  • Organizer: 第66回日本細菌学会東北支部総会
  • Place of Presentation: 仙台市
• [Presentation] TNF receptor-associated factor 5によるヘルパーT細胞制御機構の解明 (2012)
  • Author(s): 長島宏行、山木聡史、Michael Croft、石井直人、宗孝紀
  • Organizer: 第66回日本細菌学会東北支部総会
  • Place of Presentation: 仙台市
• [Presentation] L-arginine upregulates NO production by macrophages during infection with Leishmania major. (2012)
  • Author(s): Atsuko Asaoほか
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸市
• [Presentation] Homeostatic proliferation occurs in mesenteric lymph nodes and supplies effector memory CD4+ T cells in the intestine. (2012)
  • Author(s): Takeshi Kawabeほか
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸市
• [Remarks]
  • URL: http://www.immunol.med.tohoku.ac.jp//index.html