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Mechanisms of growth, survival and transformation mediated by KIT and FLT3

Research Project

Project/Area Number 13671063
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionOsaka University

Principal Investigator

KURATSUNE Hirohiko  Osaka University, Graduate School Of Medicine, Associate Professor, 医学系研究科, 助教授 (50195533)

Co-Investigator(Kenkyū-buntansha) MIZUKI Masao  Osaka University, Graduate School Of Medicine, Assistant Professor, 医学系研究科, 助手 (80283761)
MATSUMURA Itaru  Osaka University, Graduate School Of Medicine, Lecturer, 医学系研究科, 講師 (00294083)
KANAKURA Yuzuru  Osaka University, Graduate School Of Medicine, Professor, 医学系研究科, 教授 (20177489)
SHIBAYAMA Hirohiko  Osaka University, Graduate School Of Medicine, Assistant Professor, 医学系研究科, 助手 (60346202)
待井 隆志  大阪大学, 医学系研究科, 助教授 (50124780)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsReceptor tyrosine kinase / mutation / Acute myeloid leukemia / chemotaixs / Targeting therapy / STAT / inhibitor / receptor tyrosine kinase / acute myeloid leukemia / targeting therapy / KIT / PI3-K / STI571 / AG1296
Research Abstract

l. Cytoplasmic tyrosine residues involved in KIT-signal transduction
We analyzed effects of phenylalanine conversion of 22 tyrosine residues in the cytoplasmic domain on KIT-mediated cell function. In the wild type KIT, although the proliferation and survival was not affected by these Tyr->Phe conversions, the conversions of Tyr 567, 569, or 719 suppressed the cell migration mediated by KIT/SCF interaction. Tyr567 activated Src family kinase, p38 MAPkinase, which induced Ca2+ influx and the subsequent activation of Erk. Tyr 719 activated PI3-kinase, which induced Ca2+ influx. Both pathways synergistically induced the cell migration. In the constitutively active KIT mutant of kinase domain, Phe conversion of Tyr 719 abolished the kinase activity and the proliferative activity, which suggested that Tyr 719 and associated PI3-kinase is critical for kinase and transforming activity.
2. Targeting inhibition of constitutive active KITTyrosine kinase inhibitors, STI571 and AG1296 suppressed the kinase activity of juxtamembrane domain KIT mutant more effectively than wild type. In contrast, kinase domain mutant resisted to these inhibitors, even though in combination. Therefore, the sensitivity to the inhibitor differs dependent on the type of mutant.
3. FIt3 mutation specific target genes Microchip analysis revealed that Flt3 internal tandem duplication (Flt3-ITD) mutation specifically induced STAT3/5 target genes such as pim-2, SOCS3 and CIS. Flt3-ITD specifically suppressed myeloid-specific transcription factors such as C/EBPalpha and Pu. 1, which suggested that Flt3-ITD is involved in the differentiation block in AML.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Shuji Ueda: "Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis : contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration"Blood. 99. 3342-3349 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hirokazu Tanaka: "E2F-1 and c-Myc potentiate apoptosis through inhibition NF-κB that facilitates MnSOD-mediated ROS elimination"Molecular Cell. 9. 1017-1029 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Junko Sonoyama: "Functional Cooperation among Ras, STAT5, and PI3-K Is Required for Full Oncogenic Activities of BCR/ABL in K562 Cells"J. Biol. Chem. 277. 8076-8082 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shuji Ueda: "Constitutive activation of c-kit by the juxtamembrane but not the catalytic domain mutations is inhibited selectively by tyrosine kinase inhibitors STI571 and AG1296"Int. J. Hematol. 76. 427-435 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koji Hashimoto: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the D814V mutation"Blood. 101. 1094-1102 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masao Mizuki: "Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations"Blood. 101. 3164-3173 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kawasaki, A.: "Down-regulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells."J. Cell Biol.. 152. 275-288 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ueda, S.: "Critical roles of c-kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migrarion."Blood. 99. 3342-3349 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanaka,H.: "E2F-1 and c-Myc potentiate apoptosis through inhibition NF-kB that facilitates MnSOD- mediated ROS elimination."Molecular Cell. 9. 1017-1029 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ezoe, S.: "GATA-2/estrogen receptor chimeza regulates cytokine-dependent growth of hematopoiesis through accumulation of p21^<WAF>1 and p27^<KiP1> proteins."Blood. 100. 3512-3520 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sonoyama, J.: "Functional cooperation among Ras, STAT5 and PI3-K is required for full oncogenic activities of BCR/ABL in K562 cells."J. Biol. Chem.. 277. 8076-8082 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ueda, S.: "Constitutive activation of e-kit by the juxtamembrane but not the catalytic domain mutations is inhibited selectively by tyrosine kinase inhibitors STI571 and AG1296."Int J. Hematol.. 76. 427-435 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hashimoto, K.: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mecliated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the D814V mutation."Blood. 101. 1094-1102 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kawasaki, A.: "Opposing Effects of PML, and PML/RARα on STAT3 activiry."Blood. 101(9). 3668-3673

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mizuki, M.: "Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations."Blood. 101(8). 3164-3173

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 上田周二: "Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis : contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration"Blood. 99. 3342-3349 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 田中弘和: "E2F1 and c-Myc potentiate apoptosis through inhibition NF-κB that facilitates MnSOD-mediated ROS elimination"Molecular Cell. 9. 1017-1029 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 園山順子: "Functional cooperation among Ras, STAT5, and PI3 is required for full oncogenic activities of BCR/ABL in K562 cells"J.Biol.Chem. 277. 8076-8082 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 上田 周二: "Constitutive activation of c-kit by the juxtamembrane but not the catalytic domain mutations is inhibited selectively by tyrosine kinase inhibitors STI571 and AG1296"Int.J.Hematol. 76. 427-435 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 橋本光司: "Necessity of tyrosine 719 and phosphatidylinositol 3'-kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814V mutation"Blood. 101. 1094-1102 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 水木満佐央: "Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations"Blood. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fukuda, M, et al.: "Effect of transforming growth factor-beta 1 on the cell growth and Epstein-Barr virus reactivation in EBV-infected epithelial cell lines"Virology. 288. 109-118 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nojima, J, et al.: "Anti-prothrombin antibodies combined with lupus anti-coagulant activity is an essential risk factor for venous thromboembolism in patients with systemic lupus erythematosus"Br. J. Haematol. 114. 647-654 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kawasaki, A., et al.: "Down-regulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells"J. Cell. Biol.. 152. 275-288 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanaka, H., et al.: "E2F-1 and c-Myc potentiate apoptosis through inhibition NF-kB activity that facilitates MnSOD-Mediated ROS elimination"Molecular Cell. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Ueda, S., et al.: "Critical roles of c-kit tyrosine residues 567 and 719 in stem cell cell factor-induced chemotaxis : contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration"Blood. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Sonoyama, J., et al.: "Functional cooperation among Ras, STAT5, and PI3-K is required for full oncogenic activities of BCR/ABL in K562 cells"J. Biol. Chem.. (in press).

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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