1998 Fiscal Year Annual Research Report

変異ヒトG-CSFレセプタートランスジェニックマウスを用いた白血病発症機構の研究

Research Project

Project/Area Number	10152211
Research Institution	The University of Tokyo
Principal Investigator	中畑龍俊東京大学, 医科学研究所, 教授 (20110744)
Co-Investigator(Kenkyū-buntansha)	渡辺すみ子東京大学, 医科学研究所, 助手 (60240735) 辻浩一郎東京大学, 医科学研究所, 助教授 (50179991)
Keywords	M / G-CSF受容体(G-CSFR) / トランスジェニック(Tg)マウス / 造血幹細胞 / 白血病 / Kostmann症候群 / 増殖・分化 / H2-Ldプロモーター
Research Abstract	wild typeおよびC末端を欠失した変異G-CSF受容体(G-CSFR)を発現するトランスジェニックマウス(Tgマウス)を作製し、G-CSFRを介する刺激による造血幹細胞の増殖・分化過程、2種類のG-CSFRからの細胞内シグナル伝達の違いを明らかにし、白血病発症との関係を解析することを目的として行われた。本年度、H2-Ldプロモーター下流にwild typeヒトG-CSFR cDNAをつないだコンストラクトを作成し、型のごとくTgマウスを作成し、2系統のTgマウスが得られその解析を行った。リッターメイト骨髄細胞はG-CSF存在下で、好中球と少数のマクロファージのみの増殖を示したが、Tgマウス骨髄細胞をG-CSF存在下で培養すると、好中球、マクロファージばかりでなく好酸球、巨核球、肥満細胞、芽球など様々な細胞の増殖・分化・成熟が見られた。以上のG-CSFの作用はclone-sortingした細胞の培養でも確認され、G-CSFの直接作用であることが明らかとなった。さらに、ヒトG-CSF存在下で形成された芽球コロニーの再培養では、再びさまざまな血球系のコロニーが形成された。また、TgマウスへのG-CSFのin vivo投与により好中球、単球のみならず血小板の著明な増加が観察された。G-CSFのような血球系列特異的と考えられているサイトカインであっても、受容体さえ発現していれば、好中球以外の血球系列にも作用し、細胞の増殖・分化・成熟がもたらされることを考えると、血球分化におけるサイトカイン受容体シグナルの特異性は極めて低いように思われる。現在、Kostmann症候群患者で見られるG-CSFR遺伝子のmutationを持ち、C末端を欠失した2種類の変異G-CSFR-Tgマウスを作成中である。このTgマウスが作成されたら、wild typeおよび変異G-CSFR-TgマウスへのG-CSF投与により、白血病、MDSが惹起されるか否か検討する予定である。

Research Products

(27 results)

All Other

All Publications (27 results)

[Publications] Manabe A.,Mori T.,Ebihara Y.,Nakahata T.,et al: "Characterization of leukemic cells in CD2/CD19 double positive acute lymphoblastic leukemia." Int.J.Hematol.67. 45-52 (1998)
[Publications] Mukouyama Y.,Hara T.,Xu M.,Nakahata T.,et al: "Induction of hematopoiesis by oncostatin M in the AGM region." Immunity. 8. 105-114 (1998)
[Publications] Toru H.,Eguchi M.,Yata J.,Nakahata T.,et al: "IL-4 promotes the development of tryptase and chymase double positive human mast cells accompanied with cell maturation." Blood. 91. 187-195 (1998)
[Publications] Nakahata T.: "Characteristics of hemopoietic stem/progenitor cells in bone marrow,peripheral blood and cord blood." Int.J.Pediatr.Hematol.Oncology. 5. 60-61 (1998)
[Publications] Takahashi T.,Yamada K.,Nakahata T.,Hirai H.,et al: "A novel molecular approach to ex vivo hematopoietic expansion with recombinant EGER-expressing adenovirus vector." Blood. 91. 4509-4515 (1998)
[Publications] Nishihara M.,Wada Y.,Nakahata T.,Maekawa T.,et al: "A combination of stem cell factor and granulocyte colony-stimulating factor enhances the growth of human progenitor B cells supported by murine stromal cell line MS-5." Eur.J.Immunol.28. 855-864 (1998)
[Publications] Tsuji K.,Muraoka K.,Nakahata T.,et al: "Interferon-g and human megakaryopoiesis." Leukemia and Lymphoma. 31. 107-113 (1998)
[Publications] Tajika K.,Ikebuchi K.,Nakahata T.,Asano S.,et al: "IL-6 and SCF exart different effects on megakaryocyte maturation." Brit.J.Haematol.100. 105-111 (1998)
[Publications] Ishiguro A.,Ishikita T.,Naritake S.,Nakahata T.,et al: "Elevation of serum thrombopoietin precedes thrombocytopoiesis in Kawasaki disease." Thromb.Haemostasis.79. 1096-1100 (1998)
[Publications] Yoshida K.,Taga T.,Nakahata T.,Kishimoto T.,et al: "Myocardial,hematological,and placental disorders caused by targeted disruption of gp130,acommon signal transducer for IL-6 family of cytokines." Contemporary Immunology:. 259-289 (1998)
[Publications] Suzuki H.,Takei M.,Nakahata T.,Fukamachi H.,et al: "Inhibitory effect of adenosine on degranulation of human cultured mast cells upon cross-linking of FceRI." Biochem.Biophy.Res.Comm.242. 697-702 (1998)
[Publications] Sato T.,Watanabe S.,Tsuji K.,Nakahata T.,et al: "Induction of the erythropoietin receptor gene and acquisition of responsiveness to erythropoietin by stem cell factor in HML/SE,a human leukemic cell line." J.Biol.Chem.273. 16921-16926 (1998)
[Publications] Maruyama K.,Tsuji K.,Kodera Y.,Nakahata T.,et al: "Characterization of peripheral blood progenitor cells mobilized by Nartograstim(N-terminal replaced granulocyte colony-stimulating factor)in normal volunteers." Bone Marrow Transplant.22. 313-320 (1998)
[Publications] Xu M.,Tsuji K.,Miyajima A.,Nakahata T.,et al: "Stimulation of mouse and human primitive hematopoiesis by murine embryonic aorta-gonad-mesonephros-derived stromal cells." Blood. 192. 2032-2040 (1998)
[Publications] Shichijo M.,Nakahata T.,Saito H.,Nagai H.,et al: "The effect of anti-asthma drags on mediator release from cultured human mast cells." Clin.Exp.Allergy. 28. 1229-1236 (1998)
[Publications] Sako M.,Nakahata T.,Kishimoto T.,Sugiyama H.,et al: "Abnormal expression of Wilms'tumor gene WT1 in juvenile chronic myeloid leukemia and infantile monosomy 7 syndrome." Leukemia Res.22. 965-967 (1998)
[Publications] Toru H.,Pawankar R.,Yata J.,Nakahata T.,et al: "Human mast cells produce interleukin-13 by high affinity IgE receptor cross-linking:enhanced IL-13 production by IL-4 primed human mast cells." J.Allergy and Clin.Immunol.(in press).
[Publications] Yang FC,Watanabe S.,Ebihara Y.,Nakahata T.,et al: "Human G-CSF stimulates the development of primitive multipotential progenitors of human G-CSF receptor-transgenic mice,but does not affect their commitment in vitro and in vivo." Blood.92. 1632-1640 (1998)
[Publications] Nakahata T.,Sui X.,Kishimoto T.,et al: "Ex vivo expansion of human primitive hemopoietic progenitors." Stem Cells.(in press).
[Publications] Sui X.,Tsuji K.,Kishimoto T.,Nakahata T.,et al: "Soluble IL-6 receptor with IL-6 stimulates megakaryopoiesis from human CD34_+ cells through gp130 signaling." Blood. (in press).
[Publications] Yang FC.,Tsuji K.,Ikeda Y.,Nakahata T.,et al: "Effects of human granulocyte colony-stimulating factor(hG-CSF)on megakaryopoiesis and platelet function in hG-CSF receptor-transgenic mice." Blood. (in press).
[Publications] Taniguchi T.,Endo H.,Nakahata T.,Motokura T.,et al: "Expression of p21Cip1/Waf1/Sdi1 and p27 Kip1 cyclin-dependent kinase inhibitors during human hematopoiesis." Blood. (in press).
[Publications] Duraisamy K.,Saito H.,Tsuji K.,Nakahata T.,et al: "Characterization of mast-cell-committed progenitors present in human cord blood." Blood. (in press).
[Publications] Nakahata T.,Toru H.,et al: "Development of human mast cells." Adv.Immunol.(in press).
[Publications] Hasegawa S.,Nakahata T.,Okumura K.,Ra C.,et al: "Functional expression of the high affinity receptor for IgE(Fc epsilon RI)in human platelets and its intracellular expression in human megakaryocytes." Blood. (in press).
[Publications] Hibino H.,Tani K.,Nakahata T.,Asano S.,et al: "Common Mamoset as a target preclinical primate for cytokine and gene therapy studies." Blood. (in press).
[Publications] Kobayashi M.,Ueda K.,Nishihira H.,Nakahata T.,et al: "Serum granulocyte colony-stimulating factor levels in patients with chronic neutropenia of childhood:Modulation of G-CSF levels by myeloid precursor cell mass." Brit.J.Haematol.(in press).

1998 Fiscal Year Annual Research Report

変異ヒトG-CSFレセプタートランスジェニックマウスを用いた白血病発症機構の研究

Principal Investigator

中畑 龍俊 東京大学, 医科学研究所, 教授 (20110744)

Research Products

[Publications] Manabe A.,Mori T.,Ebihara Y.,Nakahata T.,et al: "Characterization of leukemic cells in CD2/CD19 double positive acute lymphoblastic leukemia." Int.J.Hematol.67. 45-52 (1998)

[Publications] Mukouyama Y.,Hara T.,Xu M.,Nakahata T.,et al: "Induction of hematopoiesis by oncostatin M in the AGM region." Immunity. 8. 105-114 (1998)

[Publications] Toru H.,Eguchi M.,Yata J.,Nakahata T.,et al: "IL-4 promotes the development of tryptase and chymase double positive human mast cells accompanied with cell maturation." Blood. 91. 187-195 (1998)

[Publications] Nakahata T.: "Characteristics of hemopoietic stem/progenitor cells in bone marrow,peripheral blood and cord blood." Int.J.Pediatr.Hematol.Oncology. 5. 60-61 (1998)

[Publications] Takahashi T.,Yamada K.,Nakahata T.,Hirai H.,et al: "A novel molecular approach to ex vivo hematopoietic expansion with recombinant EGER-expressing adenovirus vector." Blood. 91. 4509-4515 (1998)

[Publications] Nishihara M.,Wada Y.,Nakahata T.,Maekawa T.,et al: "A combination of stem cell factor and granulocyte colony-stimulating factor enhances the growth of human progenitor B cells supported by murine stromal cell line MS-5." Eur.J.Immunol.28. 855-864 (1998)

[Publications] Tsuji K.,Muraoka K.,Nakahata T.,et al: "Interferon-g and human megakaryopoiesis." Leukemia and Lymphoma. 31. 107-113 (1998)

[Publications] Tajika K.,Ikebuchi K.,Nakahata T.,Asano S.,et al: "IL-6 and SCF exart different effects on megakaryocyte maturation." Brit.J.Haematol.100. 105-111 (1998)

[Publications] Ishiguro A.,Ishikita T.,Naritake S.,Nakahata T.,et al: "Elevation of serum thrombopoietin precedes thrombocytopoiesis in Kawasaki disease." Thromb.Haemostasis.79. 1096-1100 (1998)

[Publications] Yoshida K.,Taga T.,Nakahata T.,Kishimoto T.,et al: "Myocardial,hematological,and placental disorders caused by targeted disruption of gp130,acommon signal transducer for IL-6 family of cytokines." Contemporary Immunology:. 259-289 (1998)

[Publications] Suzuki H.,Takei M.,Nakahata T.,Fukamachi H.,et al: "Inhibitory effect of adenosine on degranulation of human cultured mast cells upon cross-linking of FceRI." Biochem.Biophy.Res.Comm.242. 697-702 (1998)

[Publications] Sato T.,Watanabe S.,Tsuji K.,Nakahata T.,et al: "Induction of the erythropoietin receptor gene and acquisition of responsiveness to erythropoietin by stem cell factor in HML/SE,a human leukemic cell line." J.Biol.Chem.273. 16921-16926 (1998)

[Publications] Maruyama K.,Tsuji K.,Kodera Y.,Nakahata T.,et al: "Characterization of peripheral blood progenitor cells mobilized by Nartograstim(N-terminal replaced granulocyte colony-stimulating factor)in normal volunteers." Bone Marrow Transplant.22. 313-320 (1998)

[Publications] Xu M.,Tsuji K.,Miyajima A.,Nakahata T.,et al: "Stimulation of mouse and human primitive hematopoiesis by murine embryonic aorta-gonad-mesonephros-derived stromal cells." Blood. 192. 2032-2040 (1998)

[Publications] Shichijo M.,Nakahata T.,Saito H.,Nagai H.,et al: "The effect of anti-asthma drags on mediator release from cultured human mast cells." Clin.Exp.Allergy. 28. 1229-1236 (1998)

[Publications] Sako M.,Nakahata T.,Kishimoto T.,Sugiyama H.,et al: "Abnormal expression of Wilms'tumor gene WT1 in juvenile chronic myeloid leukemia and infantile monosomy 7 syndrome." Leukemia Res.22. 965-967 (1998)

[Publications] Toru H.,Pawankar R.,Yata J.,Nakahata T.,et al: "Human mast cells produce interleukin-13 by high affinity IgE receptor cross-linking:enhanced IL-13 production by IL-4 primed human mast cells." J.Allergy and Clin.Immunol.(in press).

[Publications] Yang FC,Watanabe S.,Ebihara Y.,Nakahata T.,et al: "Human G-CSF stimulates the development of primitive multipotential progenitors of human G-CSF receptor-transgenic mice,but does not affect their commitment in vitro and in vivo." Blood.92. 1632-1640 (1998)

[Publications] Nakahata T.,Sui X.,Kishimoto T.,et al: "Ex vivo expansion of human primitive hemopoietic progenitors." Stem Cells.(in press).

[Publications] Sui X.,Tsuji K.,Kishimoto T.,Nakahata T.,et al: "Soluble IL-6 receptor with IL-6 stimulates megakaryopoiesis from human CD34_+ cells through gp130 signaling." Blood. (in press).

[Publications] Yang FC.,Tsuji K.,Ikeda Y.,Nakahata T.,et al: "Effects of human granulocyte colony-stimulating factor(hG-CSF)on megakaryopoiesis and platelet function in hG-CSF receptor-transgenic mice." Blood. (in press).

[Publications] Taniguchi T.,Endo H.,Nakahata T.,Motokura T.,et al: "Expression of p21Cip1/Waf1/Sdi1 and p27 Kip1 cyclin-dependent kinase inhibitors during human hematopoiesis." Blood. (in press).

[Publications] Duraisamy K.,Saito H.,Tsuji K.,Nakahata T.,et al: "Characterization of mast-cell-committed progenitors present in human cord blood." Blood. (in press).

[Publications] Nakahata T.,Toru H.,et al: "Development of human mast cells." Adv.Immunol.(in press).

[Publications] Hasegawa S.,Nakahata T.,Okumura K.,Ra C.,et al: "Functional expression of the high affinity receptor for IgE(Fc epsilon RI)in human platelets and its intracellular expression in human megakaryocytes." Blood. (in press).

[Publications] Hibino H.,Tani K.,Nakahata T.,Asano S.,et al: "Common Mamoset as a target preclinical primate for cytokine and gene therapy studies." Blood. (in press).

[Publications] Kobayashi M.,Ueda K.,Nishihira H.,Nakahata T.,et al: "Serum granulocyte colony-stimulating factor levels in patients with chronic neutropenia of childhood:Modulation of G-CSF levels by myeloid precursor cell mass." Brit.J.Haematol.(in press).

中畑龍俊東京大学, 医科学研究所, 教授 (20110744)