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Research for eradication of CML stem/progenitor cells which resisted Abl kinase inhibitors

Research Project

Project/Area Number 17590987
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionHamamatsu University School of Medicine

Principal Investigator

OHNISHI Kazunori  University Hospital, Professor, 医学部附属病院, 教授 (80252170)

Co-Investigator(Kenkyū-buntansha) NAKAMURA Satoki  University Hospital, Assistant Professor, 医学部附属病院, 助手 (20377740)
SHIGENO Kazuyuki  Faculty of Medicine, Assistant Professor, 医学部, 助手 (50402251)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2005: ¥2,800,000 (Direct Cost: ¥2,800,000)
KeywordsAbl kinase inhibitor / Chronic myelogenous leukemia / colony assay / PI3K inhibitor / Bcr-Abl gene / Ablキナーゼ阻害剤 / Bcr-Abl遺伝子 / 癌 / 薬剤反応性 / 遺伝子 / シグナル伝達 / 医療・福祉
Research Abstract

Chronic myelogenous leukemia (CML) is characterized by the reciprocal chromosomal translocation (9: 22), which generates the Philadelphia (Ph) chromosome. This translocation generates a novel fusion gene, BCR-ABL, that encodes an approximately p210 protein with hyperactive tyrosine kinase activity. Bcr-Abl-expressing leukemia cells are highly resistant to apoptosis. Imatinib (STI571), an Abl kinase inhibitor, is a highly effective agent for patients with CML. However, a small percentage of these patients and most advanced-phase patients relapse on Imatinib therapy. It is poorly understood whether the Abl kinase inhibitors are able to eradicate CML progenitor or stem cells. In this study, we investigated the role of homeobox A10 (HOXA10) in CML cell lines and the hematopoietic progenitor cells derived from CML patients, and whether the regulation of HOXA10 eradicate Bcr-Abl+ hematopoietic stem/progenitor cells. The Abl kinase inhibitors and PI3K inhibitor, LY294002, induced the expression of HOXA10 in CML cell but not AML cells, and the HOXA10 induced in CML cells enhanced apoptosis. Moreover, the reduction of HOXA10 expression by siRNA in CML cells inhibited apoptosis by treatment with the Abl kinase inhibitors and LY294002. These results revealed that HOXA10 had an important role in induction of apoptosis by the Abl kinase inhibitors in CML cells. Finally, we demonstrated that the inhibition of HOXA10 expression by siRNA increased CFU-GEMM, BFU-E, and CFU-GM when the cells were treated with the combination of BMS354825 and LY294002 compared to control cells. These findings indicated that HOXA10 played a critical role in the committed colony-formation in CML. This study shows for the first time that the Abl kinase inhibitor and LY294002 induced HOXA10, and HOXA10 had an important role in apoptosis or cell growth inhibition in CML cells in vitro. The Abl kinase inhibitor and LY294002 significantly suppressed the committed colony formation in CML.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (6 results)

All 2006 2005

All Journal Article (6 results)

  • [Journal Article] Etodolac induces apoptosis and inhibits cell adhesion to bone marrow stromal cells in human myeloma cells.2006

    • Author(s)
      Nakamura S
    • Journal Title

      Leuk Res 30

      Pages: 123-135

    • Related Report
      2005 Annual Research Report
  • [Journal Article] The impact of the combination of baseline risk group and cytogenetic response on the survival of patients with chronic myeloid leukemia treated with interferon alpha.2005

    • Author(s)
      Hasford J
    • Journal Title

      Haematologica 90

      Pages: 335-340

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Etodolac inhibits EBER expression and induces Bcl-2-regulated apoptosis in Burkitt's lymphoma cells.2005

    • Author(s)
      Kobayashi M
    • Journal Title

      Eur J Haemato 75

      Pages: 212-220

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia : updated outcomes of the phase II study and postremission therapies.2005

    • Author(s)
      Shigeno K
    • Journal Title

      Int J Hematol 82

      Pages: 224-229

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Delayed recovery of normal hematopoiesis in arsenic trioxide treatment of acute promyelocytic leukemia : a comparison to all-trans retinoic acid treatment.2005

    • Author(s)
      Shinjo K
    • Journal Title

      Internal Med 44

      Pages: 818-824

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells.2005

    • Author(s)
      Takeshita A
    • Journal Title

      Leukemia 19

      Pages: 1306-1311

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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