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2003 Fiscal Year Final Research Report Summary

Molecular Mechanisms for the clonal expansion of abnormal cells in hematopoietic stem cell disorders

Research Project

Project/Area Number 14370313
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionOsaka Medical Center for Cancer and Cardiovascular Diseases

Principal Investigator

INOUE Norimitsu  Journal of Health Science, Director, 部長 (80252708)

Project Period (FY) 2002 – 2003
KeywordsParoxysmal Nocturnal Hemoglobinuria / GPI anchor / Hematopoietic stem cell / HMGA2 / Hemolytic anemia / Benign tumor / PIG-A
Research Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder characterized by the clonal expansion of glycosylphosphatidylinositol (GPI) deficient cells, leading to complement-mediated hemolysis. Several lines of evidence suggest that a somatic mutation of PIGA and additional abnormalities are necessary for the clonal expansion of the mutant clones. We propose the three-step model for the clonal expansion of the GPI deficient hematopoietic stem cells in PNH. Somatic mutation of PIG-A occurs in a hematopoietic stem cell, resulting in the deficiency of the surface expression of all GPI-anchored proteins (Step 1). Immunological attack on hematopoietic stem cells decreases the number of stem cells, positively selecting GPI-deficient cells (Step 2). In step 3, the additional somatic mutation occurs in a GPI-deficient ell, leading to further expansion and generation of a large number of GPI-anchor-deficient cells (Step 3). In this study, we reported a unique patient with PNH, whose PIGA-defective hematopoietic cells but not PIGA-normal cells, has abnormalities in both chromosomes 12 and determined the chromosomal breakpoints in this patient. Furthermore, we have identified a strong candidate gene localized at one of these breakpoints. It may be causally related to the clonal expansion of PNH clones.

  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Norimitsu Inoue: "GPI-GlcNAc Transferase (UDP-GlcNAc : PIα1-4GlcNAc transferase) : Complex of PIG-A, PIG-C, PIG-H, hGPI1 and PIG-P."Handbook of Glycosyltransferases and Their Related Genes. 533-539 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Taroh Kinoshita: "PIG-B, GPI-Man transferase III, Dol-P-Man : Man-(ethanolaminephosphate)Man-GlcN-(acyl)PI Man transferase."Handbook of Glycosyltransferases and Their Related Genes. 546-549 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Jun-ichi Nishimura: "Long-term support of hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria."Blood. 99. 2748-2751 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Taroh Kinoshita: "Relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria."Int.J.Hematology. 75. 117-122 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yeongjin Hong: "Requirement of N-glycan on GPI-anchored proteins for efficient binding aerolysin but not Clostridium septicum α-toxin."EMBO J.. 21. 5047-5056 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yashiko Murakami: "Inefficient response of T lymphocytes to Glycosylphosphatidylinositol-anchor-negative cells : implications for paroxysmal nocturnal hemoglobinuria"Blood. 100. 4116-4122 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Norimitsu Inoue: "Molecular Genetics of paroxysmal nocturnal hemoglobinuria."Int.J.Hematology. 77. 107-112 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Norimitsu Inoue: "A possible intrinsic mechanism for clonal expansion of PNH abnormal cells"Paroxysmal nocturnal hemoglobinuria and related disorders. 117-126 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yeongjin Hong: "Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that attaches GPI-anchors to proteins."Mol.Biol.Cell.. 14. 1780-1789 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kisaburo Nagamune: "GPI transamidase of Trypanosoma brucei has two novel (TTA1 and TTA2) and three common subunits."Proc.Natl.Acad.Sci.. 100. 10682-10687 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishimura, J., Hirota, T., Kanakura Y., Machii, T., Kageyama, T., Doi, S., Wada, H., Masaoka, T., Kanayama, Y., Fujii, H., Inoue, N., Kuwayama, M., Inoue, N., Ohishi, K., Kinoshita, T.: "Long-term support of hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria."Blood. 99(8). 2748-2751 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kinoshita, T., Inoue, N.: "Relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria"Int.J.Hematology. 75(2). 117-122 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hong, Y., Ohishi, K., Inoue, N., Kang, J.Y., Shime, H., Horiguchi, Y., van der Goot, F.G., Sugimoto, N., Kinoshita, T.: "Requirement of N-glycan on GPI-anchored proteins for efficient binding aerolysin but not Clostridium septicum α-toxin."EMBO J.. 21(19). 5047-5056 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Murakami, Y., Kosaka, H., Maeda, Y., Nishimura, J., Inoue, N., Ohishi, K., Okabe, M., Takeda, J., Kinoshita: Blood. 100(12). 4116-4122 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Inoue, N., Murakami, Y., Kinoshita, T.: "Molecular Genetics of paroxysmal nocturnal hemoglobinuria."Int.J.Hematology. 77(2). 107-112 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hong, Y., Ohishi, K., Kang, J.Y., Tanaka, S., Inoue, N., Nishimura, J-I., Maeda, Y., Kinoshita, T.: "Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that attaches GPI-anchors to proteins."Mol.Biol.Cell.. 14. 1780-1789 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagamune, K., Ohishi, K., Ashida, H., Hong, Y., Hino, J., Kangawa, K., Inoue, N., Maeda, Y., Kinoshita, T.: "GPI transamidase of Trypanosoma brucei has two novel (TTA1 and TTA2) and three common subunits."Proc.Natl.Acad.Sci.. 100(19). 10682-10687 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Inoue, N., Kinoshita, T.: "GPI-GlcNAc Transferase (UDP-GlcNAc : Plα1-4GlcNAc transferase) : Complex of PIG-A, PIG-C, PIG-H, hGPI1 and PIG-P.(Handbook of Glycosyltransferases and Their Related Genes)(Eds. N.Taniguchi, K.Honke and M.Fukuda)"Springer-Verlag. 535-539 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kinoshita, T., Inoue, N.: "PIG-B, GPI-Man transferase III, Dol-P-Man : Man-(ethanolaminephosphate)Man-GlcN-(acyl)PI Man transferase.(Handbook of Glycosyltransferases and Their Related Genes)(Eds. N.Taniguchi, K.Honke and M.Fukuda)"Springer-Verlag. 546-519 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Inoue, N., Izui, T., Kuwayama, M., Nishimura, J-I., Kurokawa, K., Machii, T., Kanakura Y., Kinoshita, T.: "A possible intrinsic mechanism for clonal expansion of PNH abnormal cells(Paroxysmal nocturnal hemoglobinuria and related disorders)(Eds. M.Omine and T.Kinoshita)"Springer-Verlag. 126 (2003)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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