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Hematopoietic Cell Maturation Is Regulated by Maintaining a Balance against Cytokine Induced-Cell Proliferation - Clinical Application for Differentiation-inducing Therapy of Leukemia-

Research Project

Project/Area Number 09671135
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionTokyo Medical University

Principal Investigator

MIYAZAWA Keisuke  Department of Medicine, Tokyo Medical University, Associate Professor, 医学部, 講師 (50209897)

Co-Investigator(Kenkyū-buntansha) YAGUCHI Makoto  Department of Medicine, Tokyo Medical University, Associate Professor, 医学部, 助手 (50246310)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1998: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1997: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsHematopoiesis / Cell Growth / Differentiation / Cytokine / Leukemia / Differentiation-inducing therapy / Hematopoietic growth factor
Research Abstract

Using a factor-dependent cell line MO7ER, which contains a stably transduced human erythropoietin (EPO) receptor gene in human megakaryoblastic cell line MO7e and which resulted in concomitant expression of EPO receptor, c-Mpl and c-Kit, we investigated the biological effects of these cytokines in terms of cell growth and differentiation. Thrombopoietin (TPO), EPO and Steel factor (SLF) all stimulated MO7ER cell proliferation in a dose-dependent manner. Combined stimulation of cells with SLF plus either TPO or EPO resulted in striking synergistic enhancement of MO7ER cell growth as compared with each cytokine alone, whereas combination of TPO plus EPO showed only an additive effect on cell proliferation. With regards * cell differentiation, either TPO or EPO treatment induced enhancement of platelet glycoprotein (GP) IIb/IIIa and GPIb expression. SLF induced GPIIb/IIIa and GPIb expression, but the effect was much weaker than that of EPO or TPO. However, addition of SLF to either TPO- o … More r EPO-containing cultures (which induced potent mitogenesis in MO7ER cells) resulted in suppression of these megakaryocyte specific antigens. Addition of low-dose cytosine arabinoside (Ara-C)(1 to 10 ng/ml) enhanced TPO- or EPO- induced megakaryocytic differentiation in MO7ER cells while mildly suppressing cell growth. Treatment the cells with low-dose Ara-C plus TPO plus SLF overrode the proliferative enhancing effects of SLF and induced GPIIb/IIIa and GPIb expression as efficient as TPO alone. Retardation of TPO-induced megakaryocytic maturation was also observed in normal murine bone marrow cells by combined stimulation with TPO and SLF as assessed by the numbers of acetylcholinesterase staining-positive cells and megakaryocyte nuclear polyploidy. In addition, combination of low-dose Ara-C plus G-CSF enhanced granulocytic differentiation in WEHI-3B cells, as compared with the cells treated with G-CSF alone. This phenomenon was also reproduced using the primary cultured leukemia cells which were isolated from the patients with various types of acute myelogenous leukemias,
These results suggest that hematopoietic cell maturation is, at least in part, regulated by countering cytokine-induced cell proliferation. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Yaguchi M,Miyazawa K,et al.: "Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance of all-trans retinoic acid."Leukemia. 11. 779-787 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tauchi T,Miyazawa K,et al.: "A colied-coil tetramerization domain of BCR-ABL is essential for the interaction of SH2-ontaining signal transduction molecules."Human Cell. 9. 333-336 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yaguchi M,Miyazawa K,et al.: "Vitamin K2 therapy for a patient with myelodysplastic syndrome."Leukmeia. 13. 144-145 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Miyazawa K: "Book review: Hematopoitic stem cells."Int J Hematol.. 68. 337-338 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nishimaki J,Miyazawa K,et al.: "Vitamin K2 induces apoptosis odf a novel cell line established from a patient with myelodysplastic syndrome."Leikemia. (in press). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Gotoh A,Reid S,Miyazawa K,et al.: "SDF-1 suppresses cytokine-induced adhesion of human hematopoietic progenitor cells to immobilized firbronectin."Brit J Haematol. (in press). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yaguchi M, Miyazawa K, Katagiri T, Nishimaki J, Kizaki M, Tohyama K, Toyama K: "Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance of all-trans retinoic acid. 17."Leukemia. 11. 779-787 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tauchi T, Miyazawa K, K Ohyashiki, Toyama K: "A coiled-coil tetramerization domain of BCR-ABL is essential for the interaction of SH2-ontaining signal transduction molecules"Human Cell. 9. 333-336 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Uchida Y, Miyazawa K, Yaguchi M, Gotoh A, Iwase O, Ohyashiki K, Toyama K: "Establishment of a novel B-lymphoma cell line, CTB-1, with strong Fas antigen expression having chromosomal translocation (14;22)"Int. J. Oncol.. 10. 1103-1107 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yaguchi M, Miyazawa K, Otawa M, Katagiri T, Nishimaki J, Uchida Y, Iwase O, Gotoh A, Kawanishi Y, Toyama K: "Vitamin K2 selectively induces apoptosis of blastic cells in myelodysplastic syndrome: flow cytometric detection of apoptotic cells using APO2.7 monoclonal antibody"Leukemia. 12. 1392-1397 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yahata N, Ohyashiki K, Ohyashiki J, Kimura Y, Miyazawa K, Kodama A, Fukutake K, Toyama K: "Late apperarance of t(5;12)(q31;p12) in acute myeloid leukmeia associated with eosinophilia"Cancer Genet Cttogenet. 107. 147-150 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Miyazawa K: "Book review: Hematopoitic stem cells. 22. Yaguchi M"Int J Hematol.. 68. 337-338 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yaguchi M, Miyazawa K, Otawa M, Ito Y, Kawanishi N, Toyama K: "Vitamin K2 therapy for a patient with myelodysplastic syndrome"Leukmeia. 13. 144-145 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Katagiri T, Miyazawa K, Uchida Y, Shigehumi H, Iwama H, Shyoji N, Kawakubo K, Shimamoto T, Inatomi Y, Kuriyama Y, Yaguchi M, Nehashi Y, Ohyashiki K, Toyama K: "Induction of Ph-negative clone and long-term survival by combined treatment with G-CSF plus middle dose cytosine arabinoside for patients with chronic myeloid leukemia in blastic transformation"Jpn J Clin Hematol.. 39. 1149-1156 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Suzuki A, Miyazawa K, Katagiri T, Shyoji N, Nishimaki J, Iwase O, Itoh K, Tauchi T, Kawanishi K, Kimura Y, Nakano S, Toyama K: "A Trial for peripheral blood stem cell harvest by combination of G-CSF with ABVD regimen in the management of Hodgikin's disease"Jpn J Clin Hematol.. 40. 16-21 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yaguchi M, Miyazawa K et al.: "Vitamin K2 selectively induces apoptisis of blaotic cells in myelodyas plastic syndrome:flow cytometric detection of apototic cells using APO2・7 monoclonal antibody" Leukemia. 18・9. 1392-1397 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Miyazawa K.: "Hematopoietic stem cells" Int.J.Hematol.68・1. 337-338 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yaguchi M,Miyazawa K et al: "Vitemin K2 therapy for a patient with myelodysplastic syndrome" Leukemia. 13・1. 144-145 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yahata N et al.: "Late applarance of t(15;12)(q31;p12)in acute myeloid leukemia,associated with eosinophilia." Cancer Genet. Cytogenet. 107・2. 147-150 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 片桐智子,宮澤啓介他: "急性転化後、rhG-CSF併用Cytosine Arabinoside中等量の化学療法により正常核型細胞出現と12ヶ月以上の生存が得られた慢性骨髄性白血病" 臨床血液. 39・12. 1149-1156 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 鈴木章孝,宮澤啓介他: "Hody kin病におけるABVD療法+G-CSF併用による末梢血幹細胞採取の試み" 臨床血液. 40・1. 16-21 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yaguchi M,Miyazawa K.et al.: "Vitamin K2 and its derivatives induce apoptosis in leukemia cells and enhance. the effect of all-trans retinoic acid." Leukemia. 11・5. 779-787 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Uchida Y,Miyazawa K et al.: "Establishment of a novel B-lymphoma cell line,CTB-1,with strong Fas antigen expression having chromosomal translocation(14;22)." Int.J.Oncol.10・8. 1103-1107 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Miyazawa K,Nishimaki J.et al.: "Megakaryocytic maturation is regulated by maintaining a balance against cytokine induced-cell proliferation:Steel factor retards thrombopoietin-induced megakaryocytic differentiation while synergistially stimulating mitogenesis." Cell Growth & Differentiation. (in press).

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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