Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors
Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors
复制标题
DOI：
10.1128/mcb.24.14.6172-6183.2004
复制
发表时间：
2004-07-01
影响因子：
5.3
通讯作者：
Inaba, T
中科院分区：
文献类型：
--
作者：
Kuribara, R;Honda, H;Inaba, T
已知Bcr-AbI激酶逆转由于细胞因子剥夺引起的嘌呤依赖性细胞的凋亡，尽管慢性髓性白血病（CML）祖细胞是否具有在存在有限量的细胞因子的条件下存活的潜力一直存在争议。在这里，我们证明，早期hernatopoietic祖细胞（Sca-1（+）c-Kit（+）Lin（-））分离自正常小鼠在细胞因子的情况下迅速经历凋亡。在这些细胞中，诱导Bim的表达，Bim是Bcl-2的促凋亡相对物，其在姜黄素介导的存活系统中起关键作用。相反，从我们先前建立的CML模型小鼠中分离的那些细胞在不诱导Bim表达的情况下在无精氨酸培养基中抵抗凋亡，并且这些作用被AbI特异性激酶抑制剂甲磺酸伊马替尼逆转。此外，Bim的表达水平在从CML的急变期患者建立的细胞系中一致较低，伊马替尼在这些细胞中诱导Bim。此外，降低Bim表达水平的小干扰RNA有效地挽救CML细胞免于伊马替尼引起的凋亡。这些研究结果表明，Bim在早期造血祖细胞的凋亡中起着重要作用，Bcr-AbI部分通过下调这种细胞死亡激活剂来支持细胞存活。
Bcr-AbI 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 hernatopoietic 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 AbI-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-AbI supports cell survival in part through downregulation of this cell death activator.