Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition
Apoptosis and erythroid differentiation triggered by Bcr-Abl inhibitors in CML cell lines are fully distinguishable processes that exhibit different sensitivity to caspase inhibition
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DOI：
10.1038/sj.onc.1210034
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发表时间：
2007-04-12
期刊：
影响因子：
8
通讯作者：
Auberger, P.
中科院分区：
文献类型：
--
作者：
Jacquel, A.;Colosetti, P.;Auberger, P.
伊马替尼靶向导致人类慢性髓性白血病（CML）的Bcr-Abl癌基因。最近，我们证明了伊马替尼除了触发K562细胞凋亡外，还介导了它们的红细胞分化。尽管这两个事件似乎是同时发生的，但目前尚不清楚伊马替尼诱导的细胞凋亡和分化是否相互依赖。因此，我们研究了Bcr-Abl抑制剂介导的细胞凋亡和红细胞分化对几种已建立和工程CML细胞系的需求。伊马替尼可触发不同CML细胞系的凋亡和红系分化，但只有凋亡对zvd -fmk抑制敏感。相反，p38丝裂原活化蛋白（MAP）激酶抑制剂SB202190在不影响caspase激活的情况下显著减缓红系分化。此外，伊马替尼和另一种Bcr-Abl抑制分子PD166326可触发K562细胞克隆的红系分化，但对Bcr-Abl抑制剂诱导的凋亡具有抗性。最后，短发夹RNA抑制剂（shRNAi）沉默caspase 3有效抑制caspase活性，但对红细胞分化没有影响，而Bcr-Abl沉默模拟伊马替尼或PD166326处理，导致K562细胞凋亡和红细胞分化增加。综上所述，我们的研究结果不仅表明Bcr-Abl抑制剂介导的细胞凋亡和分化是完全可区分的事件，而且表明半胱天冬酶对于已建立的CML细胞系的红系分化是必不可少的。
Imatinib targets the Bcr-Abl oncogene that causes chronic myelogenous leukemia (CML) in humans. Recently, we demonstrated that besides triggering apoptosis in K562 cells, imatinib also mediated their erythroid differentiation. Although both events appear to proceed concomitantly, it is not known at present whether or not imatinib-induced apoptosis and differentiation are interdependent processes. Hence, we investigated the requirements for Bcr-Abl inhibitor-mediated apoptosis and erythroid differentiation in several established and engineered CML cell lines. Imatinib triggered apoptosis and erythroid differentiation of different CML cell lines, but only apoptosis exhibited sensitivity to ZVAD-fmk inhibition. Conversely, the p38 mitogen-activated protein (MAP) kinase inhibitor, SB202190, significantly slowed down erythroid differentiation without affecting caspase activation. Furthermore, imatinib and PD166326, another Bcr-Abl inhibitory molecule, triggered erythroid differentiation of K562 cell clones, nevertheless resistant to Bcr-Abl inhibitor-induced apoptosis. Finally, short hairpin RNA inhibitor (shRNAi) silencing of caspase 3 efficiently inhibited caspase activity but had no effect on erythroid differentiation, whereas silencing of Bcr-Abl mimicked imatinib or PD166326 treatment, leading to increased apoptosis and erythroid differentiation of K562 cells. Taken together, our findings not only demonstrate that Bcr-Abl inhibitor-mediated apoptosis and differentiation are fully distinguishable events, but also that caspases are dispensable for erythroid differentiation of established CML cell lines.