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Epidemiological and molecular biological study of myelodysplastic syndrome (MDS) among atomic bomb survivors

Research Project

Project/Area Number 11480141
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 環境影響評価(含放射線生物学)
Research InstitutionHIROSHIMA UNIVERSITY

Principal Investigator

KIMURA Akiro  Hiroshima University, Research Institute for Radiation Biology and Medicine, Professor, 原爆放射能医学研究所, 教授 (70127645)

Co-Investigator(Kenkyū-buntansha) TANAKA Hideo  Hiroshima University, Research Institute for Radiation Biology and Medicine, Associate Professor, 原爆放射能医学研究所, 助教授 (50243613)
HAYAKAWA Norihiko  Hiroshima University, Research Institute for Radiation Biology and Medicine, Professor, 原爆放射能医学研究所, 教授 (40022834)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2000: ¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsMDS / Atomic bomb / Radiation / AML 1 / DNA repair / 放射線 / 被爆 / 被爆者 / 被曝 / 被曝者
Research Abstract

To study the effect of radiation exposure on MDS development among Hiroshima A bomb survivors, patients with definite individual radiation dose were examined between 1985 and 1999. The dose was estimated according to ABS 93 dosimetry system. Among 735 patients without malignancy, 26 patients aged from 48 to 88 (median : 75) had diagnosis of MDS, including 16 RA, 2 RARS, 4 RAEB and 4 RAEBt. We analyzed the relative risk in relation to exposed radiation dose using a multiple regression with Cox proportional hazard model. Highly significant dose-effect on the risk of MDS was found. The relative risk was 2.53 (95 % CI : 1.49-4.30) at the dose of 100 cSv against 0 cSv (P = 0.0006). Age at the time of bombing showed significant effects on the risk (P = 0.0000). This is the first time that the incidence of hematological disease other than leukemia was found to be radiation dose dependent.
In order to clarify the molecular mechanism of A bomb radiation-induced MDS/AML, we studied the mutations of AML 1 which plays important roles in the definitive hematopoiesis by forming the transcription factor complex with CBF β. We have analyzed the DNA-binding domain (the runt domain) of AML 1 gene for mutations by PCR-SSCP assay using genomic DNA from bone marrow samples followed by sequence analysis. AML 1 mutations were identified in 46 % (6/13) of A bomb radiation-exposed MDS patients. Two cases had silent mutations (P157syn and T101syn), 3 cases had missense mutations (G42R, D171N and G42R), and one case had a frame shift/nonsense mutation (L70del 1bp to stop). In addition, missense mutations were found in 2/3 radiotherapy-related MDS/AML patients. On the other hand, AML 1 mutations were found in only 2.9 % (2/70) of sporadic MDS cases. The high incidence of AML 1 gene mutations in radiation-associated MDS/AML suggested that dysregulation of AML 1 function plays pivotal roles in this category of hematopoietic disorders.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] 木村昭郎: "骨髄異形成症候群(MDS)「血液・造血器疾患・免疫機構の障害」"日本臨床 本邦臨床統計集(1). 59(増刊号7). 504-544 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harada, Y. et al.: "A hematopoietic-specific transmembrane protein, Art-1, is possibly requlated by AML1"Biochem.Bioph.Res.Com.. 284(3). 714-722 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kimura, A. et al.: "Atomic bomb radiation enhances the risk of MDS"Leukemia Research. 25(Suppl). S13 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harada, Y. et al.: "Somatic mutations of the AML1 gene are frequent in therapyrelated and rediation-associated myelodysplastic syndrome/acute myeloid leukemia(MDS/AML)"Blood. 98(11). 567a (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 蔵本 憲 他: "放射線リスクの高い血液疾患:骨髄異形成症候群"放射線生物研究. (印刷中). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ban, S.et al.: "Radiosensitivity and expression of nucleotide excision repair genes in peripheral blood mononuclear cells of myelodysplastic syndrome patients"Int.Congress Series. 730(in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 木村昭郎: "インフォームドコンセントガイダンス-血液疾患診療編-"先端医学社. 493 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harigae, H., et al.: "A novel mutation of the erythroid-specific δ -aminolaevulinate synthase gene in a patient with X-linked sideroblastic anaemia"Br. J. Haematol.. 106. 175-177 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Harigae, H et al.: "Two novel mutations of the 5 δ -aminolaevulinate synthase-2 gene in innherited and non-inherited sideroblastic anemia"Blood. 94. 191a (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kuramoto, K., et al.: "ZK7, a novel zinc finger gene, is induced by vascular endothelial growth factor and inhibits apoptotic death in hematopoietic cells"Cancer Res.. 60. 425-430 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kimura, A., et al.: "Strong radiation effect for myelodysplastic syndrome (MDS) among atomic bomb survivors"Int. J. Hematol. 72. 110 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Oguma, N., et al.: "Various response patterns of Ph1 cells to IFN-α in patients with chronic myelocytic leukemia"Exp. Oncol.. 22. 73-77 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujii, T., et al.: "A new approach to detect reticulated platelets stained with thiazole orange in thrombocytopenic patients"Thrombo. Res.. 97. 431-440 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nobuyoshi, M., et al.: "Arrest human dendritic cells at the CD34-/CD4+/HLA-DR+ stage in the bone marrow of NOD/SCID-human chimeric mice"Blood. 97. 3655-3657 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka, H., et al.: "Acute myelogenous leukemia with PIG-A gene mutation evolved from aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome"Int. J. Hematol. 73. 206-212 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 木村昭郎: "骨髄異形成症候群(MDS)「血液・造血器疾患・免疫機構の障害」"日本臨床 本邦臨床統計集(1). 59(増刊号7). 504-544 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Harada, H., et al.: "A hematopoietic-specific transmembrane protein, art-1, is possibly requlated by AML1"Biochem Biophys Res Commun. 284(3). 714-722 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Katayama, Y., et al.: "Lack of allelic exclusion and isotype class swithing in B cell chronic lymphocytic leukemia"Am. J. Hematol.. 68(4). 295-297 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kimura, A.: "Atomic bomb radiation enhances the risk of MDS"Leukemia Res.. 25(Sup.1). S13 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Harada., et al.: "Somatic mutations of the AML1 gene are frequent in therapy-related and radiation-associated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)"Blood. 98(11). 567a (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 木村昭郎: "インフォームド・コンセントガイダンス-血液疾患診療編-(月本一郎編)"慢性骨髄性白血病患者へのインフォームド・コンセントの進め方. 1-394 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kimura,A., et al: "Strong radiation effect for myelodysplastic syndrome (MDS) among atomic bomb survivors."Int.J.Hematol. 72(Sup.1). 110 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Harada,H., et al: "The AML1/ETO fusion protein represses erythroid cell differentiation, and downregulates a novel hematopoietic-specific transmembrane protein, ART-1."Blood. 96(Part 1). 669a (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Katayama,Y., et al: "Lack of allelic exclusion and isotype class swithing in B cell chronic lymphocytic leukemia."Blood. 96(Part 2). 277b (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanaka,H., et al : "Acute myelogenous leukemia with PIG-A gene mutation evolved fromaplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome."Int.J.Hematol. 73. 206-212 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Oguma,N., et al: "Various response patterns of Ph^1 cells to IFN-α in patients with chronic myelocytic leukemia."Exp.Oncol.. 22. 73-77 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Harigae, H et al: "A novel mutation of the erythroid-specific δ-aminolaevulinate synthase gene in a patient with X-linked sideroblastic anaemia."Br. J. Haematol. 106. 175-177 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 小田健司 他: "急速な汎血球減少を呈した骨髄腺維化を伴う骨髄異形成症候群の1例"広島医学. 52. 948-951 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 阿部和弘 他: "橋本病を合併し,高γグロブリン血症を伴った直接被爆者の骨髄異形成症候群の1症例"広島医学. 52. 231-234 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kuramoto, K., et al: "ZK7, a novel zinc finger gene, is induced by vascular endothelial growth factor and inhibits apoptotic death in hematopoietic cells."Cancer Res.. 60. 425-430 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Harigae, H.、 et al: "Two novel mutations of the δ-aminolevulinate synthase-2 gene in innherited and non-inherited sideroblastic anemia."Blood. 94. 191a (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nobuyoshi, M., et al: "Human dendritic cell precursors in nod/scid mice transplanted with human cord blood mononuclear cells."Blood. 94. 572a (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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