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Development of new methods in diagnosis and treatment of tumors by the targeting of chimeric protein

Research Project

Project/Area Number 08557018
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Human pathology
Research InstitutionThe University of Tokyo

Principal Investigator

MORI Shigeo  The University of Tokyo, The Institiute of Medical Science, Professor, 医科学研究所, 教授 (30010424)

Co-Investigator(Kenkyū-buntansha) WATANABE Toshiki  The University of Tokyo, The Institiute of Medical Science, Associate Professor, 医科学研究所, 助教授 (30182934)
YAMAMOTO Tadashi  The University of Tokyo, The Institiute of Medical Science, Professor, 医科学研究所, 教授 (40134621)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥15,500,000 (Direct Cost: ¥15,500,000)
Fiscal Year 1998: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1997: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 1996: ¥7,500,000 (Direct Cost: ¥7,500,000)
Keywordsmalignant lymphoma / BCL6 gene / chromosomal translocation / mRNA / chimeric protein / リンパ腫 / 染色体 / p80NPM / ALK / キメラ蛋白質 / 未分化大細胞型リンパ腫 / ALK遺伝子 / TLS / CHOP遺伝子 / bcl6遺伝子
Research Abstract

The chimeric gene is a unique non-natural gene made by the fusion of two different genes, causing production of a novel protein with the head and tail parts made of two different genes. Some of such chimeric protein cause specific diseases like soft part sarcoma and malignant lymphomas. This study was aimed (1)to identify new pathogenetic chimeric genes/proteins, (2)Biological function of chimeric proteins, (3)Application of chimeric proteins in the diagnosis and treatment of human diseases.
(1) Identification of new pathogenetic chimeric genes/proteins :
Over 20 chimeric genes were identified from human malignant lymphomas a part of which was derived from BCL6 gene. Some of them were found to be new genes. Also, a new type of TLS/FUS-CHOP chimeric gene was identified from human liposarcoma tissues.
(2) Biological function of chimeric proteins :
A part of the biological functions of NPM/ALK chimeric protein was clarified. Also, the biological function of BCL6 gene product was partly clarified.
(3) Application of chimeric proteins in the diagnosis and treatment of human diseases :
With the introduction of newly developed antibody to NPM/ALK chimeric protein, we invested an easy and conclusive diagnostic method for the NPM/ALK chimera-related human diseases. Also, we could transfer over 20 cases of human malignant lymphomas bearing different types of chimera genes. This cell line is now under study for the targeting of these genes in immunotherapy.

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (47 results)

All Other

All Publications (47 results)

  • [Publications] Yee HT: "Molecular characterization of the t (2 ; 5) (p23 ; q35) translocation in anaplastic large cell lymphoma (Ki-1) and Hodgkin's disease." Blood. 87. 1081-88 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Lamant,M: "High incidence of the t (2 ; 5) (p23 ; q35) translocation in anaplastic large cell lymphoma and the lack of detection in Hodgkin's disease." Blood. 87. 284-291 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Moriyama N: "BCL-6 is phosphorylated at multiple sites in its serine-and proline-clustered region by mitogen-activated protein kinase MAPK)in vivo." Oncogene. 14. 2465-74 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamochi T: "Regulation of BCL-6 gene expression in human myeloid/monocytoid leukemic cells." Leukemia. 11. 694-700 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Watanabe H: "Chondrocytes as a specific target of ectopic Fos expression in early development." Proc Natl Acad Sci USA. 94. 3994-3999 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Peliri SA: "Frequent expression of the NPM/ALK chimeric fusion protein in anaplastic large cell lymphoma,Lympho-histiocytic type." Am J Pathol. 150. 1207-11 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] L D.Su: "Headington and T.Singleton : The t (2 ; 5) -associated p80NPM/ALK fusion protein in nodal and cutaneous CD30+lymphoproliferative disorders." J Cutan Path. 24. 597-603 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamochi T: "Adenovirus-mediated high expression of BCL-6 in CV-1 cells induces apoptotic cell death accompanied by down-regulation of BCL-2 and BCL-XL." Oncogene. (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] Iwahara T: "Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system." Oncogene.14(4). 439-49 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fujimoto J: "Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t (2 ; 5)." Proc Natl Acad Sci USA. 93(9). 4181-6 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Horie R: "A novel domain in the CD30 cytoplasmic tail mediates NFkappaB activation." Intern Immunol. 10(2). 203-10 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuroda M: "Oncogenic transformation and inhibition of adipocytic conversion of preadipocytes by TLS/FUS-CHOP type II chimeric protein." Am J Path. 151(3). 735-44 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Aizawa S: "Tumor necrosis factor receptor-associated factor (TRAF) 5 and TRAF2 are involved in CD30-mediated NFkappaB activation." J Biol Chem. 272(4). 2042-5 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Aizawa S: "Cloning and characterization of a cDNA for rat CD30 homolog and chromosomal assignment of the genomic gene." Gene. 182(1-2). 155-62 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ishida T: "Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region." J Biol Chem. 271(46). 28745-8 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Horie R: "A variant CD30 protein lacking extracellular and transmembrane domains is induced in HL-60 by tetradecanoylphorbol acetate and is expressed in alveolar macrophages." Blood. 88(7). 2422-32 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yee HT,Ponzoni M,Merson A,Goldstein M,Scarpa A,Chilosi M,Menestrina F,Pittaluga, S,Wolf-Peeters CD,Shiota M,Mori S,Frizzera G,Inghirami G: "Molecular characterization of the t (2 ; 5) (p23 ; q35) translocation in anaplastic large cell lymphoma (ki-l) and Hodgkin's disease" Blood. 87. 1081-1088 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Lamant, M., Megetto, F., Saati, T.A., Brugieres, L., Shiota, S., Mori, S.and Delsol, G.: "High incidence of the t (2 ; 5) (p23 ; q35) translocation in anaplastic large cell lymphoma and the lack of detection in Hodgkin's disease" Blood. 87. 284-291 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Moriyama N,Yamochi T,Semba K,Akiyama T and Mori S: "BCL-6 is phosphorylated at multiple sites in its serine-and proline-clustered region by mitogen-activated protein kinase MAPK) in vivo." Oncogene. 14. 2465-2474 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamochi T,Kitabayashi A,Hirokawa M,Miura A,Onizuka T,Mori S,and Moriyama M: "Regulation of BCL-6 gene expression in human myeloid/monocytoid leukemic cells." Leukemia. 11. 694-700 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Watanabe H,Saitoh K,Kameda T,Murakami M,Niikura Y,Okazaki S,Morishita Y,Mori S,Yokouchi Y,Kuroiwa A and Iba H: "Chondrocytes as a specific target of ectopic Fos expression in early development." Proc Natl Acad Sci USA. 94. 3994-3999 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Peliri SA,Pulford K,Mori S,Mason DY,Sabattini E,Roncador G,Piccioli M,Ceccarelli C,Piccaluga PP,Santini D,Leone O,Stein H,Falini B: "Frequent expression of the NPM/ALK chimeric fusion protein in anaplastic large cell lymphoma, Lympho-histiocytic type." Am J Pathol. 150. 1207-1211 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] L D.Su, B Schnitzer, C W.Ross, M Vasef, S Mori, M Shiota, DY.Mason, K Pulford, JT Headington and T.Singleton: "The t (2 ; 5) -associated p80NPM/ALK fusion protein in nodal and cutaneous CD30+ lymphoproliferative disorders." J Cutan Path. 24. 597-603 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamochi T,Kaneita Y,Akiyama T,Mori S,Moriyama M: "Adenovirus-mediated high expression of BCL-6 in CV-1 cells induces apoptotic cell death accompanied by down-regulation of BCL-2 and BCL-XL." Oncogene. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Iwahara T.Fujimoto J.Wen D.Cupples R.Bucay N.Arakawa T.Mori S.Ratzkin B.Yamamoto T: "Molecular characterization of ALK,a receptor tyrosine kinase expressed specifically in the nervous system." Oncogene. 14 (4). 439-449 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fujimoto J.Shiota M.Iwahara T.Seki N.Satoh H.Mori S.Yamamoto T: "Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t (2 ; 5)." Proc Natl Acad Sci USA. 93 (9). 4181-4186 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Horie R.Aizawa S.Nagai M.Ito K.Higashihara M.Ishida T.Inoue J.Watanabe T: "A novel doman in the CD30 cytoplasmic tail mediates NFkappaB activation." Intern Immunol. 10 (2). 203-210 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuroda M.Ishida T.Takanashi M.Satoh M.Machinami R.Watanabe T: "Oncogenic transformation and inhibition of adipocytic conversion of preadipocytes by TLS/FUS-CHOP type II chimeric protein." Am J Path. 151 (3). 735-744 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Aizawa S.Nakano H.Ishida T.Horie R.Nagai M.Ito K.Yagita H.Okumura K.Inoue J.Watanabe T: "Tumor necrosis factor receptor-associated factor (TRAF) 5 and TRAF2 are involved in CD30-mediated NFkappaB activation." J Biol Chem. 272 (4). 2042-2045 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Aizawa S.Satoh H.Horie R.Ito K.Choi SH.Takeuchi H.Watanabe T: "Cloning and characterization of a cDNA for rat CD30 homolog and chromosomal assignment of the genomic gene." Gene. 182 (1-2). 155-162 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ishida T.Mizushima Si.Azuma S.Kobayashi N.Tojo T.Suzuki K.Aizawa S.Watanabe T.Mosialos G.Kieff E.Yamamoto T.Inoue J: "Identification of TRAF6, a novel tumor necrosis factor recrptor-associated factor protein that mediated signaling from an amino-terminal domain of the CD40 cytoplasmic region." J Biol Chem. 271 (46). 28745-28748 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Horie R.Ito K.Tatewaki M.Nagai M.Aizawa S.Higashihara M.Ishida T.Inoue J.Takizawa H.Watanabe T: "A variand CD30 protein lacking extracellular and transmembrane domains is induced in HL-60 by tetradecanoylphorbol acetate and is expressed in alveolar macrophages." Blood. 88 (7). 2422-2432 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamochi T: "Adenovirus-mediated high expression of BCL-6 in CV-1 cells induces apoptotic cell death accompanied by down-regulation of BCL-2 and BCL-XL." Oncogene. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mori S.: "Malignant lymphoma in immunocompromized hosts" Gann Monograph on Cancer Res.155-160 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Katano H.: "Establishment and characterization of a CD30-positive cell line harboring HHV-8 from primary effusion lymphoma." Medical Virology. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Iwahara T, Mori S, Yamamoto T: "Molecular characterization of ALK,a receptor tyrosine kinase expressed specifically in the nervous system" Oncogene. 14. 439-449 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamochi T, Mori S: "Regulation of BCL-6 gene expression in human mgeloid 1 monocytoid leukemic cells" Leukemia. 11. 694-700 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Moriyama T, Mori S: "BCL-6 is phosphorylated at multiple sites in its serine-and proline-clustered region by MAPK in vioo" Oncogene. 14. 2465-2474 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Peliri SA, Mori S: "Frequent expression of the NPM/ALK chimeric fusion protein in anaplasitic large cell lymphoma,lymphohistiocytic type" American Journal of Pathology. 150. 1207-1211 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nakagawa A, Mori S: "CD30-positive panaplastic large cell lymphoma in childhood" Moderm Pathology. 10. 210-215 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Watanabe H, Mori S: "Chondrocyte as a speciflc target of ectopic Fos expression in early development" Proc Natl Acad Sci USA. 94. 3994-3999 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yee HT,Ponzoni M,Merson A,Mori S,Frizzera G,Inghirami G: "Molecular characterization of the t(2;5)(p23;q35)translocation in anaplastic large cell lymphoma(Ki-1)and Hodgkin's disease." Blood. 87. 1081-88 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Lamant,M.,Megetto,F.,Mori,S.and Delsol,G.: "High incidence of the t(2;5)(p23;q35)translocation in anaplastic large cell lymphoma and the lack of detection in Hodgkin's disease." Blood. 87. 284-291 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Fujimoto J,Shiota M,Mori S,Yamamoto T: "Characterization of the transforming activity of p80,ahyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation(2;5)" Proc Natl Acad Sci USA. 93. 4181-4186 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Iwahara T,Fujimoto J,Mori S,Yamamoto T: "Molecular characterization of ALK,a receptor tyrosine kinase expressed specifically in the nervous system." Oncogene. 14. 439-49 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Moriyama N,Yamochi T,Akiyama T and Mori S: "BCL-6 is phosphorylated at multiple sites in its serine-and proline-clustered region by mitogen-activated protein kinase MAPK) in vivo" Oncogene. (in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Watanabe H,Saitoh K,Mori S,Yokouchi Y,: "Chondrocytes as a specific target of ectopic Fos expression in early development" Proc Natl Acad Sci USA. (in press). (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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