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Molecular and Cellular Biology, July 2004, p. 6172-6183, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6172-6183.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Ryoko Kuribara,1 Hiroaki Honda,2 Hirotaka Matsui,3 Tetsuharu Shinjyo,4 Takeshi Inukai,5 Kanji Sugita,5 Shinpei Nakazawa,5 Hisamaru Hirai,6 Keiya Ozawa,1 and Toshiya Inaba3*

Department of Hematology, Jichi Medical School, Tochigi 329-0498,1 Departments of Developmental Biology,2 Molecular Oncology, Research Institute for Radiation BiologyMedicine, Hiroshima University, Hiroshima 734-8553,3 2nd Department of Internal Medicine, University of Ryukyus, Okinawa 903-0215,4 Department of Pediatrics, University of Yamanashi, Yamanashi 409-3898,5 Department of Hematology/Oncology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan6

Received 27 June 2003/ Returned for modification 27 August 2003/ Accepted 21 April 2004

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.

* Corresponding author. Mailing address: Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Phone: 81-82-257-5834. Fax: 81-82-256-7103. E-mail: tinaba{at}hiroshima-u.ac.jp.

Molecular and Cellular Biology, July 2004, p. 6172-6183, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6172-6183.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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