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Mechanism of leukemogenesis with chromosomal translocation induced by oncogenic fusion genes and proliferation-associated genes

Research Project

Project/Area Number 15390322
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionKyoto Prefectural University of Medicine (2004-2005)
The University of Tokyo (2003)

Principal Investigator

TAKI Tomohiko  Kyoto Pref.Univ.of Med., Grad.Sch.of Med.Sci., Dept of Mol.Lab.Med., Associate Professor, 医学研究科, 講師 (50322053)

Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥8,600,000 (Direct Cost: ¥8,600,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2004: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2003: ¥3,800,000 (Direct Cost: ¥3,800,000)
Keywordsleukemia / chromosomal translocation / chimeric gene / proliferation-associated gene / MLL / FLT3 / KIT / t(8;21) / 遺伝子 / 癌 / チロシンキナーゼ / 細胞・組織 / 急性白血病 / PDGFRA / c-KIT / FLT3
Research Abstract

We analyzed a complex translocation involving chromosomes 7, 11, 19 and 22 in infant acute monocytic leukemia, and identified that the MLL gene on 11q23 was fused to the unconventional myosin type 1F, MYO1F, gene on 19p13.2-13.3. The MYO1F gene bears no homology with the partner genes of MLL previously described, therefore, this finding would provide new insights into leukemogenesis associated with MLL.
We next performed mutational analysis of FLT3 genes in childhood acute lymphoblastic leukemia (ALL), and found FLT3-D835/I836 mutations in 8(18.2%) of 44 infants with ALL with MLL rearrangements. In mouse model, MLL-SEPT6 induced myeloproliferative disease with long latency, but not acute leukemia. We developed in vitro and in vivo model systems of leukemogenesis by MLL fusion proteins, where activated FMS-like receptor tyrosine kinase 3(FLT3) together with MLL-SEPT6 not only transformed hematopoietic progenitors in vitro but also induced acute biphenotypic or myeloid leukemia with short latency in vivo. These findings showed direct evidence for a multistep leukemogenesis mediated by MLL fusion proteins and may be applicable to development of direct MLL fusion-targeted therapy.
We also performed mutational analysis of KIT and FLT3 genes in childhood acute myeloid leukemia (AML) with t(8;21), and found the kinase domain mutations of the KIT gene in 8 (17.4%) of 46 patients. FLT3 internal tandem duplication was found in only 2 (4.3%) patients. Significant differences between patients with or without KIT mutations were observed in the 4-year overall survival (50.0% versus 97.4%, P<0.001), disease-free survival (37.5% versus 94.7%, P<0.001) and relapse rate (47.0% versus 2.7%, P<0.001). Although patients with t(8;21)-AML are generally considered to have a good prognosis, these results suggested that KIT mutations are strongly associated with a poor prognosis in pediatric t(8;21)-AML.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (39 results)

All 2006 2005 2004 2003 Other

All Journal Article (31 results) Book (2 results) Publications (6 results)

  • [Journal Article] Chromosomal translocations in cancer and their relevance for therapy.2006

    • Author(s)
      Taki T, Taniwaki M.
    • Journal Title

      Current Opinion in Oncology 18

      Pages: 62-68

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] KIT mutation, and not FLT3 internal tandem duplication, is strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21) : a study of the Japanese Childhood AML Cooperative Study Group.2006

    • Author(s)
      Shimada A, Taki T, et al.
    • Journal Title

      Blood 107

      Pages: 1806-1809

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies.2006

    • Author(s)
      Chen Y, Taki T, et al.
    • Journal Title

      Genes, Chromosomes and Cancer 45

      Pages: 583-591

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Chromosomal translocations in cancer and their relevance for therapy.2006

    • Author(s)
      Taki T, Taniwaki M.
    • Journal Title

      Curr Opin Oncol 18

      Pages: 62-68

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] KIT mutation, and not FLT3 internal tandem duplication, is strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21) : a study of the Japanese Childhood AML Cooperative Study Group.2006

    • Author(s)
      Shimada A, Taki T, Tabuchi K, Tawa A, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y.
    • Journal Title

      Blood 107

      Pages: 1806-1809

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Mutations of the PTPN 11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies.2006

    • Author(s)
      Chen Y, Takita J, Hiwatari M, Igarashi T, Hanada R, Kikuchi A, Hongo T, Taki T, Ogasawara M, Shimada A, Hayashi Y.
    • Journal Title

      Genes Chromosomes Cancer 45

      Pages: 583-591

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Chromosomal translocaions in cancer and their relevance for therapy.2006

    • Author(s)
      Taki T, Taniwaki M.
    • Journal Title

      Current Opinion in Oncology 18

      Pages: 62-68

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Mutations in the tyrosine kinase domain of the platelet-derived growth factor receptor_(PDGFRA) gene in childhood acute myeloid leukemia with t(8;21)(q22;q22) or inv(16)(p13q22).2005

    • Author(s)
      Hiwatari M, Taki T, et al.
    • Journal Title

      Leukemia 19

      Pages: 476-477

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple lineage leukemogenesis.2005

    • Author(s)
      Ono R, Taki T, et al.
    • Journal Title

      Journal of Clinical Investigation 115

      Pages: 919-929

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Infertility with defective spermiogenesis in mice lacking AF5q31, the target of chromosomal translocation in human infant leukemia.2005

    • Author(s)
      Urano A, Taki T, et al.
    • Journal Title

      Molecular and Cellular Biology 25

      Pages: 6834-6845

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Identification of a chromosomal breakpoint and detection of a novel form of MLL-AF17 fusion transcript in acute myelomonocytic leukemia with t(11;17)(q23;q21)2005

    • Author(s)
      Suzukawa K, Taki, et al.
    • Journal Title

      International Journal of Hematology 82

      Pages: 38-41

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The MYO1F, unconventional myosin type 1F, gene is fused to MLL in infant acute monocytic leukemia with a complex translocation involving chromosomes 7, 11, 19 and 22.2005

    • Author(s)
      Taki T, Akiyama M, et al.
    • Journal Title

      Oncogene 24

      Pages: 5191-5197

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Disruption of Sept6, a fusion partner gene of MLL, does not affect ontogeny, leukemogenesis induced by MLL-SEPT6, or phenotype induced by the loss of Sept4.2005

    • Author(s)
      Ono R, Taki T, et al.
    • Journal Title

      Molecular and Cellular Biology 25

      Pages: 10965-10978

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Mutations in the tyrosine kinase domain of the platelet-derived growth factor receptor α(PDGFRA) gene in childhood acute myeloid leukemia with t(8;21)(q22;q22) or inv(16)(p13g22).2005

    • Author(s)
      Hiwatari M, Taki T, Tsuchida M, Hanada R, Hongo T, Sako M, Hayashi Y.
    • Journal Title

      Leukemia 19

      Pages: 476-477

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple lineage leukemogenesis.2005

    • Author(s)
      Ono R, Nakajima H, Ozaki K, Kumagai H, Kawashima T, Taki T, Kitamura T, Hayashi Y, Nosaka T.
    • Journal Title

      J Clin Invest 115

      Pages: 919-929

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Infertility with defective spermiogenesis in mice lacking AF5q31, the target of chromosomal translocation in human infant leukemia.2005

    • Author(s)
      Urano A, Endoh M, Wada T, Morikawa Y, Itoh M, Kataoka Y, Taki T, Akazawa H, Nakajima H, Komuro I, Yoshida N, Hayashi Y, Handa H, Kitamura T, Nosaka T.
    • Journal Title

      Mol Cell Biol 25

      Pages: 6834-6845

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Identification of a chromosomal breakpoint and detection of a novel form of MLL-AF17 fusion transcript in acute myelomonocytic leukemia with t(11;17)(q23;q21).2005

    • Author(s)
      Suzukawa K, Shimizu S, Nemoto N, Takei N, Taki T, Nagasawa T.
    • Journal Title

      Int J Hematol 82

      Pages: 38-41

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The MYO1F, unconventional myosin type 1F, gene is fused to MLL in infant acute monocytic leukemia with a complex translocation involving chromosomes 7, 11, 19 and 22.2005

    • Author(s)
      Taki T, Akiyama M, Saito S, Ono R, Taniwaki M, Kato Y, Yuza Y, Eto Y, Hayashi Y.
    • Journal Title

      Oncogene 24

      Pages: 5191-5197

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Disruption of Sept6, a fusion partner gene of MLL, does not affect ontogeny, leukemogenesis induced by MLL-SEPT6, or phenotype induced by the loss of Sept4.2005

    • Author(s)
      Ono R, Ihara M, Nakajima H, Ozaki K, Kataoka-Fujiwara Y, Taki T, Nagata K, Inagaki M, Yoshida N, Kitamura T, Hayashi Y, Kinoshita M, Nosaka T.
    • Journal Title

      Mol Cell Biol 25

      Pages: 10965-10978

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The MYO1F, unconventional myosin type 1F, gene is fused to MLL in infant acute monocytic leukemia with a complex translocation involving chromosomes 7,11,19 and 22.2005

    • Author(s)
      Taki T, Akiyama M, et al.
    • Journal Title

      Oncogene 24

      Pages: 5191-5197

    • Related Report
      2005 Annual Research Report
  • [Journal Article] In vitro drug resistance to imatinib and mutation of ABL gene in childhood Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia.2005

    • Author(s)
      Kawaguchi H, Taki T, et al.
    • Journal Title

      Leukemia and Lymphoma 46

      Pages: 273-276

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mutations in the tyrosine kinase domain of the platelet-derived growth factor receptor a (PDGFRA) gene in childhood acute myeloid leukemia with t(8;21)(q22;q22) or inv(16)(p13q22).2005

    • Author(s)
      Hiwatari M, Taki T, et al.
    • Journal Title

      Leukemia 19

      Pages: 476-477

    • Related Report
      2004 Annual Research Report
  • [Journal Article] FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangement and pediatric ALL with hyperdiploidy.2004

    • Author(s)
      Taketani T, Taki T, et al.
    • Journal Title

      Blood 103

      Pages: 1085-1088

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangement and pediatric ALL with hyperdiploidy.2004

    • Author(s)
      Taketani T, Taki T, Ishii E, Hanada R, Tsuchida M, Sugita K, Sugita K, Hayashi Y.
    • Journal Title

      Blood 103

      Pages: 1085-1088

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Characterization of genomic breakpoints in MLL and CBP in leukemia patients with t(11;16).2004

    • Author(s)
      Zhang Y, Taki T, et al.
    • Journal Title

      Genes, Chromosomes, and Cancer 41

      Pages: 257-265

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements.2003

    • Author(s)
      Tsutsumi S, Taki T, et al.
    • Journal Title

      Cancer Research 63

      Pages: 4882-4887

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome.2003

    • Author(s)
      Xu G, Taki T, et al.
    • Journal Title

      Blood 102

      Pages: 2960-2668

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements.2003

    • Author(s)
      Tsutsumi S, Taketani T, Nishimura K, Ge X, Taki T, Sugita K, Ishii E, Hanada R, Ohki M, Aburatani H, Hayashi Y.
    • Journal Title

      Cancer Res 63

      Pages: 4882-4887

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome.2003

    • Author(s)
      Xu G, Kanezaki R, Told T, Hayashi Y, Kamio T, Terui K, Taketani T, Taki T, Mitui T, Koike K, Kato K, Imaizumi M, Sekine I, Ikeda Y, Hanada R, Sako M, Kudo N, Kojima S, Yamamoto M, Ito E.
    • Journal Title

      Blood 102

      Pages: 2960-2968

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple lineage leukemogenesis.

    • Author(s)
      Ono R, Taki T, et al.
    • Journal Title

      Journal of Clinical Investigation (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The MYO1F, unconventional myosin type 1F, gene is fused to MLL in infant acute monocytic leukemia with a complex translocation involving chromosomes 7,11,19 and 22.

    • Author(s)
      Taki T, et al.
    • Journal Title

      Oncogene (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Book] 血液腫瘍-MIC-M診断から治療まで-2005

    • Author(s)
      編著 谷脇雅史, 分担 滝 智彦
    • Total Pages
      300
    • Publisher
      先端医学社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 血液膿瘍-MIC-M診断から治療まで-2005

    • Author(s)
      編著 谷脇雅史 分担 滝 智彦
    • Total Pages
      300
    • Publisher
      先端医学社
    • Related Report
      2005 Annual Research Report
  • [Publications] Hiwatari M, Taki T, et al.: "Fusion of an AF4-related gene, LAF4, to MLL in childhood acute lymphoblastic leukemia with t(2;11)(q11;q23)."Oncogene. 22. 2851-2855 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Echlin-Bell DR, Taki T, et al.: "Polymorphisms in the MLL breakpoint cluster region (BCR)."Hum Genet. 113. 80-91 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Taketani T, Taki T, et al.: "AML1/RUNX1 mutations are infrequent, but related to AML-M0, acquired trisomy 21, and leukemic transformation in pediatric hematological malignancies."Geves Chromosomes Cancer. 38. 1-7 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tsutsumi S, Taki T, et al.: "Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements."Cancer Res. 63. 4882-4887 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Xu G, Taki T, et al.: "Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome."Blood. 102. 2960-2968 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Taketani T, Taki T, et al.: "FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangement and pediatric ALL with hyperdiploidy."Blood. 103. 1085-1088 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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