1997 Fiscal Year Annual Research Report

サイトカインを介した造血幹細胞の増殖と分化の制御機構の解析

Research Project

Project/Area Number	09250211
Research Institution	Kyushu University
Principal Investigator	仁保喜之九州大学, 医学部, 教授 (60091287)
Co-Investigator(Kenkyū-buntansha)	浅野嘉延九州大学, 医学部, 助手 (60271110) 権藤久司九州大学, 医学部, 助手 (10253428) 岡村孝九州大学, 医学部, 助手 (30136436) 岡村精一九州大学, 医学部, 講師 (20136435)
Keywords	G-CSF / G-CSF受容体 / 細胞内シグナル伝達蛋白 / 先天性好中球減少症 / 骨髄性白血病 / 点突然変異 / IL-10 / 可溶性G-CSF受容体
Research Abstract	造血幹細胞の増殖と分化は各種のサイトカインにより絶妙に制御されている。これらのサイトカインの刺激伝達経路に異常が生ずれば、種々の造血異常症が引き起こされる可能性が考えられる。これまでに我々は、遺伝子の点突然変異によりG-CSF受容体の細胞内領域に異常を来した先天性好中球減少症を利用して、G-CSF受容体の構造異常が好中球減少症の病因となり得ることを証明した。続いて、骨髄性白血病の発症や進展にもG-CSF刺激伝達経路の構造異常が関与している可能性を考え、100例近い骨髄症白血病(急性骨髄性白血病、骨髄異形成症候群、慢性骨髄性白血病、慢性好中球性白血病)の症例において、G-CSF受容体の細胞内領域を中心にPCR-SSCP法にて構造異常を検討した。異常が疑われた症例では塩基配列を解析したが、病因となり得る変異は認めなかった。しかし、intron 14にGがAへ変異する遺伝子多型を発見した。この遺伝子多型は正常人100名中11名に認め、多型マーカーとして利用されることが期待された。現在は、G-CSF受容体より下流の細胞内シグナル伝達蛋白に拡大して、構造異常を検討中である。一方、骨髄性白血病の一部の症例では白血病細胞自身がG-CSFを産生し、G-CSFを介して自己増殖している。そこで、G-CSFの産生と刺激伝達経路を標的とした白血病細胞の増殖抑制効果を検討した。IL-10は白血病細胞からのG-CSF産生を阻害し、可溶性G-CSF受容体はG-CSFと受容体の結合を競合的に阻害することで、白血病細胞の自己増殖を抑制した。現在、細胞内シグナル伝達蛋白の阻害薬による白血病細胞の増殖抑制効果を解析中である。このように、サイトカインの刺激伝達経路を標的とした新しい治療法の開発が期待される。

Research Products

(22 results)

All Other

All Publications (22 results)

[Publications] Asano Y.: "Effect of (-)-epigallocatechin gallate on leukemic blast cells from patients with acute myeloblastic leukemia." Life Sciences. 60(2). 135-142 (1997)
[Publications] Higuchi M.: "Membrane tumor necrosis factor-α(TNF- α )expressed on HTL-I-infected T cells mediates a costimulatory signal for B cell activation-characterization of membrane TNF-α." Clin.Immunol.Immunopath.82(2). 133-140 (1997)
[Publications] Takenaka K.: "Increased incidence of cytomegalovirus(CMV)infection and CMV-associated disease after allogeneic bone marrow transplantation from unrelated donors." Bone Marrow Transplant.19. 241-248 (1997)
[Publications] Katayama Y.: "The effects of a simplified method for cryopreservation and thawing procedures on peripheral blood cells." Bone Marrow Transplant.19. 283-287 (1997)
[Publications] Miyamoto T.: "Collection and transplantation autologous peripheral blood stem cells in adults." Jpn.J.Apheresis. 16(1). 50-55 (1997)
[Publications] Ikeda K.: "C5a induces tissue factor activity on endothelial cells." Thromb.Haemost.77(2). 394-398 (1997)
[Publications] Miyamoto T.: "Significance of quantitative analysis of AML1/ETO transcripts in peripheral blood stem cells from t(8;21)." Leukemia & Lymphoma. 25. 69-75 (1997)
[Publications] Niiro H.: "Regulation by interleukin-10 and interleukin-4 of cyclooxygenase-2 expression in human neutrophils." Blood. 89(5). 1621-1628 (1997)
[Publications] Kanaji T.: "Molecular and genetic analysis of two patients with Bernard-Soulier syndrome - identification of new mutations in glycoprotein Ib α gene." Thromb.Haemost.77. 1055-1061 (1997)
[Publications] Akashi T.: "Direct evidence for the contribution of B cells to the progression of insulitis and the development of diabetes in non-obese diabetic mice." Int.Immunol.9(8). 1159-1164 (1997)
[Publications] Asano Y.: "Effect of the chimeric soluble granulocyte colony-stimulating factor receptor on the proliferation of leukemic blast cells." Cancer Res.57. 3395-3397 (1997)
[Publications] Fujishima H.: "Inhibition by 5-fluorouracil of ERCC1 and γ-glutamylcysteine synthetase messenger RNA expression in a cisplatin resistant HST-1 human squamous carcinoma cell line." Oncology Res.9. 167-172 (1997)
[Publications] Shigematsu H.: "Role of the vav proto-oncogene product(Vav)in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity." J.Biol.Chem.272(22). 14334-14340 (1997)
[Publications] Yoshizawa S.: "A thermolabile β2-macroglycoprotein(TMG)and the antibody against TMG in patients with systemic lupus erythematosus." Clinica Chimica Acta. 264. 219-225 (1997)
[Publications] Tanaka Y.: "Detection of polymorphisms within the human IL-10 receptor DNA gene sequence by RT-PCR RFLP." Immunogenetics. 46. 439-441 (1997)
[Publications] Gondo H.: "Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia." Bone Marrow Transplant.20. 821-826 (1997)
[Publications] Asano Y.: "IL-10 inhibits the autocrine growth of leukemic blast cells from patients with acute myeloblastic leukemia." Int.J.Hematol.66. 445-450 (1997)
[Publications] Yamaoka K.: "Activation of STAT5 by lipopolysaccharide through granulocyte-macrophage colonystimulating factor production in human monocytes." J.Immunol.160. 838-845 (1998)
[Publications] Horiuchi T.: "A non-sense mutation at Arg^<95> is predominant in complement 9 deficiency in Japanese." J.Immunol.160. 1509-1513 (1998)
[Publications] Shibata S.: "Analysis of the granulocyte colony-stimulating factor receptor gene structure using PCR-SSCP in the myeloidlLeukemia and myelodysplastic syndrome." Eur.J.Haematol.(in press). (1998)
[Publications] Niho Y.: "Fas/Fas ligant and hematopoietic precursor cells." Curr.Opin.Hematol.(in press). (1998)
[Publications] Asano Y.: "Action of interleukein-3 on the proliferation of leukemic progenitor cells from patients with acute myeloblastic leukemia." Clin.Lab.Haematol.(in press). (1998)

1997 Fiscal Year Annual Research Report

サイトカインを介した造血幹細胞の増殖と分化の制御機構の解析

Principal Investigator

仁保 喜之 九州大学, 医学部, 教授 (60091287)

Research Products

[Publications] Asano Y.: "Effect of (-)-epigallocatechin gallate on leukemic blast cells from patients with acute myeloblastic leukemia." Life Sciences. 60(2). 135-142 (1997)

[Publications] Higuchi M.: "Membrane tumor necrosis factor-α(TNF- α )expressed on HTL-I-infected T cells mediates a costimulatory signal for B cell activation-characterization of membrane TNF-α." Clin.Immunol.Immunopath.82(2). 133-140 (1997)

[Publications] Takenaka K.: "Increased incidence of cytomegalovirus(CMV)infection and CMV-associated disease after allogeneic bone marrow transplantation from unrelated donors." Bone Marrow Transplant.19. 241-248 (1997)

[Publications] Katayama Y.: "The effects of a simplified method for cryopreservation and thawing procedures on peripheral blood cells." Bone Marrow Transplant.19. 283-287 (1997)

[Publications] Miyamoto T.: "Collection and transplantation autologous peripheral blood stem cells in adults." Jpn.J.Apheresis. 16(1). 50-55 (1997)

[Publications] Ikeda K.: "C5a induces tissue factor activity on endothelial cells." Thromb.Haemost.77(2). 394-398 (1997)

[Publications] Miyamoto T.: "Significance of quantitative analysis of AML1/ETO transcripts in peripheral blood stem cells from t(8;21)." Leukemia & Lymphoma. 25. 69-75 (1997)

[Publications] Niiro H.: "Regulation by interleukin-10 and interleukin-4 of cyclooxygenase-2 expression in human neutrophils." Blood. 89(5). 1621-1628 (1997)

[Publications] Kanaji T.: "Molecular and genetic analysis of two patients with Bernard-Soulier syndrome - identification of new mutations in glycoprotein Ib α gene." Thromb.Haemost.77. 1055-1061 (1997)

[Publications] Akashi T.: "Direct evidence for the contribution of B cells to the progression of insulitis and the development of diabetes in non-obese diabetic mice." Int.Immunol.9(8). 1159-1164 (1997)

[Publications] Asano Y.: "Effect of the chimeric soluble granulocyte colony-stimulating factor receptor on the proliferation of leukemic blast cells." Cancer Res.57. 3395-3397 (1997)

[Publications] Fujishima H.: "Inhibition by 5-fluorouracil of ERCC1 and γ-glutamylcysteine synthetase messenger RNA expression in a cisplatin resistant HST-1 human squamous carcinoma cell line." Oncology Res.9. 167-172 (1997)

[Publications] Shigematsu H.: "Role of the vav proto-oncogene product(Vav)in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity." J.Biol.Chem.272(22). 14334-14340 (1997)

[Publications] Yoshizawa S.: "A thermolabile β2-macroglycoprotein(TMG)and the antibody against TMG in patients with systemic lupus erythematosus." Clinica Chimica Acta. 264. 219-225 (1997)

[Publications] Tanaka Y.: "Detection of polymorphisms within the human IL-10 receptor DNA gene sequence by RT-PCR RFLP." Immunogenetics. 46. 439-441 (1997)

[Publications] Gondo H.: "Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia." Bone Marrow Transplant.20. 821-826 (1997)

[Publications] Asano Y.: "IL-10 inhibits the autocrine growth of leukemic blast cells from patients with acute myeloblastic leukemia." Int.J.Hematol.66. 445-450 (1997)

[Publications] Yamaoka K.: "Activation of STAT5 by lipopolysaccharide through granulocyte-macrophage colonystimulating factor production in human monocytes." J.Immunol.160. 838-845 (1998)

[Publications] Horiuchi T.: "A non-sense mutation at Arg^<95> is predominant in complement 9 deficiency in Japanese." J.Immunol.160. 1509-1513 (1998)

[Publications] Shibata S.: "Analysis of the granulocyte colony-stimulating factor receptor gene structure using PCR-SSCP in the myeloidlLeukemia and myelodysplastic syndrome." Eur.J.Haematol.(in press). (1998)

[Publications] Niho Y.: "Fas/Fas ligant and hematopoietic precursor cells." Curr.Opin.Hematol.(in press). (1998)

[Publications] Asano Y.: "Action of interleukein-3 on the proliferation of leukemic progenitor cells from patients with acute myeloblastic leukemia." Clin.Lab.Haematol.(in press). (1998)

仁保喜之九州大学, 医学部, 教授 (60091287)