Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors.
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.
Kuribara
Ryoko
R
Department of Hematology, Jichi Medical School, Tochigi, Japan.
Honda
Hiroaki
H
Matsui
Hirotaka
H
Shinjyo
Tetsuharu
T
Inukai
Takeshi
T
Sugita
Kanji
K
Nakazawa
Shinpei
S
Hirai
Hisamaru
H
Ozawa
Keiya
K
Inaba
Toshiya
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001549:Benzamides; D015415:Biomarkers; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism
D001549:Benzamides; D015415:Biomarkers; D016207:Cytokines; D004791:Enzyme Inhibitors; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D020928:Mitogen-Activated Protein Kinases