Roles of Bim in Apoptosis of Normal and Bcr-Abl-Expressing Hematopoietic Progenitors

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  • Ryoko Kuribara
    Department of Hematology, Jichi Medical School, Tochigi 329-0498
  • Hiroaki Honda
    Departments of Developmental Biology
  • Hirotaka Matsui
    Molecular Oncology, Research Institute for Radiation Biology Medicine, Hiroshima University, Hiroshima 734-8553
  • Tetsuharu Shinjyo
    2nd Department of Internal Medicine, University of Ryukyus, Okinawa 903-0215
  • Takeshi Inukai
    Department of Pediatrics, University of Yamanashi, Yamanashi 409-3898
  • Kanji Sugita
    Department of Pediatrics, University of Yamanashi, Yamanashi 409-3898
  • Shinpei Nakazawa
    Department of Pediatrics, University of Yamanashi, Yamanashi 409-3898
  • Hisamaru Hirai
    Department of Hematology/Oncology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
  • Keiya Ozawa
    Department of Hematology, Jichi Medical School, Tochigi 329-0498
  • Toshiya Inaba
    Molecular Oncology, Research Institute for Radiation Biology Medicine, Hiroshima University, Hiroshima 734-8553

説明

Bcr-Abl kinase is known to reverse apoptosis of cytokine-dependent cells due to cytokine deprivation, although it has been controversial whether chronic myeloid leukemia (CML) progenitors have the potential to survive under conditions in which there are limited amounts of cytokines. Here we demonstrate that early hematopoietic progenitors (Sca-1(+) c-Kit(+) Lin(-)) isolated from normal mice rapidly undergo apoptosis in the absence of cytokines. In these cells, the expression of Bim, a proapoptotic relative of Bcl-2 which plays a key role in the cytokine-mediated survival system, is induced. In contrast, those cells isolated from our previously established CML model mice resist apoptosis in cytokine-free medium without the induction of Bim expression, and these effects are reversed by the Abl-specific kinase inhibitor imatinib mesylate. In addition, the expression levels of Bim are uniformly low in cell lines established from patients in the blast crisis phase of CML, and imatinib induced Bim in these cells. Moreover, small interfering RNA that reduces the expression level of Bim effectively rescues CML cells from apoptosis caused by imatinib. These findings suggest that Bim plays an important role in the apoptosis of early hematopoietic progenitors and that Bcr-Abl supports cell survival in part through downregulation of this cell death activator.

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