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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Switching leukemia cell phenotype between life and death.
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Switching leukemia cell phenotype between life and death.

机译：在生与死之间切换白血病细胞表型。

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Divergent life or death responses of a cell can be controlled by a single cytokine (tumor necrosis factor alpha, TNF) via the signaling pathways that respond to activation of its two receptors (TNFR1 and TNFR2). Here, we show that the choice of life or death can be controlled by manipulation of TNFR signals. In human erythroleukemia patient myeloid progenitor stem cells (TF-1) as well as chronic myelogenous leukemia cells (K562), granulocyte-macrophage colony-stimulating factor primes cells for apoptosis. These death-responsive cells show prolonged TNF stimulation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but no NF-kappaB transcriptional activity as a consequence of receptor-interacting protein degradation by caspases. Conversely, cells of a proliferative phenotype display antiapoptotic NF-kappaB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects. These proliferative effects of TNF are apparently due to enhanced basal expression of the caspase-8/FLICE-inhibitory protein FLIP. Manipulation of the NF-kappaB, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinase signals switches leukemia cells from a proliferative to an apoptotic phenotype; consequently, these highly proliferative cells die rapidly. In addition, sodium salicylate mimics the death phenotype signals and causes selective destruction of leukemia cells. These findings reveal the signaling mechanisms underlying the phenomenon of human leukemia cell life/death switching. Additionally, through knowledge of the signals that control TNF life/death switching, we have identified several therapeutic targets for selectively killing these cells.
机译：单个细胞因子（肿瘤坏死因子α，TNF）可以通过响应其两个受体（TNFR1和TNFR2）激活的信号通路来控制细胞的不同生死反应。在这里，我们表明可以通过操纵TNFR信号来控制生死的选择。在人类红细胞白血病患者的骨髓祖细胞（TF-1）以及慢性粒细胞白血病细胞（K562）中，粒细胞-巨噬细胞集落刺激因子启动细胞凋亡。这些死亡反应性细胞显示出c-Jun N末端激酶和p38丝裂原活化蛋白激酶的TNF刺激时间延长，但由于半胱天冬酶与受体相互作用的蛋白降解，因此没有NF-κB转录活性。相反，具有增殖表型的细胞显示抗凋亡的NF-κB反应，拮抗c-Jun N端激酶和p38丝裂原活化的蛋白激酶应激激酶效应。 TNF的这些增殖作用显然是由于caspase-8 / FLICE抑制蛋白FLIP的基础表达增强所致。 NF-κB，c-Jun N-末端激酶或p38丝裂原活化的蛋白激酶信号的操纵将白血病细胞从增殖表型转变为凋亡表型。因此，这些高度增殖的细胞迅速死亡。另外，水杨酸钠模仿死亡表型信号并引起白血病细胞的选择性破坏。这些发现揭示了人类白血病细胞生命/死亡转换现象的潜在信号传导机制。此外，通过了解控制TNF寿命/死亡切换的信号，我们确定了选择性杀死这些细胞的几种治疗靶标。

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