Faderl Stefan, Harris David, Van Quin, Kantarjian Hagop M, Talpaz Moshe, Estrov Zeev
Department of Leukemia,, The University of Texas M. D. Anderson Cancer Center, Houston, USA.
Blood. 2003 Jul 15;102(2):630-7. doi: 10.1182/blood-2002-06-1890. Epub 2003 Mar 27.
High levels of cytokines are associated with a poor prognosis in acute myeloid leukemia (AML). However, cytokines may induce, on one hand, survival factor expression and cell proliferation and, on the other hand, expression of inhibitory signals such as up-regulation of suppressors of cytokine signaling (SOCS) and induce apoptotic cell death. Because blasts from patients with AML express high procaspase protein levels, we asked whether granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances procaspase protein production in AML cells. In the GM-CSF-responsive OCIM2 AML cell line, GM-CSF induced signal transducer and activator of transcription 5 (Stat 5) phosphorylation, up-regulated cyclin D2, and stimulated cell cycle progression. Concurrently, GM-CSF stimulated expression of SOCS-2 and -3 and of procaspases 2 and 3 and induced caspase 3 activation, poly(ADP[adenosine 5'-diphosphate]-ribose) polymerase (PARP) cleavage, and apoptotic cell death. The Janus kinase (Jak)-Stat inhibitor AG490 abrogated GM-CSF-induced expression of procaspase 3 and activation of caspase 3. Under the same conditions GM-CSF up-regulated production of BAX as well as Bcl-2, Bcl-XL, survivin, and XIAP. GM-CSF also increased procaspase 3 protein levels in OCI/AML3 and Mo7e cells, suggesting that this phenomenon is not restricted to a single leukemia cell line. Our data suggest that GM-CSF exerts a dual effect: it stimulates cell division but contemporaneously up-regulates Jak-Stat-dependent proapoptotic proteins. Up-regulation of procaspase levels in AML is thus a beacon for an ongoing growth-stimulatory signal.
细胞因子水平升高与急性髓系白血病（AML）的不良预后相关。然而，细胞因子一方面可诱导生存因子表达和细胞增殖，另一方面可诱导抑制性信号的表达，如细胞因子信号转导抑制因子（SOCS）的上调，并诱导凋亡性细胞死亡。由于AML患者的原始细胞表达高水平的前半胱天冬酶蛋白，我们研究粒细胞-巨噬细胞集落刺激因子（GM-CSF）是否能增强AML细胞中前半胱天冬酶蛋白的产生。在对GM-CSF有反应的OCIM2 AML细胞系中，GM-CSF诱导信号转导和转录激活因子5（Stat 5）磷酸化，上调细胞周期蛋白D2，并刺激细胞周期进程。同时，GM-CSF刺激SOCS-2和-3以及前半胱天冬酶2和3的表达，并诱导半胱天冬酶3激活、聚（ADP[腺苷5'-二磷酸]-核糖）聚合酶（PARP）裂解和凋亡性细胞死亡。Janus激酶（Jak）-Stat抑制剂AG490可消除GM-CSF诱导的前半胱天冬酶3表达和半胱天冬酶3激活。在相同条件下，GM-CSF上调BAX以及Bcl-2、Bcl-XL、生存素和XIAP的产生。GM-CSF还增加了OCI/AML3和Mo7e细胞中前半胱天冬酶3蛋白水平，表明这种现象并不局限于单一白血病细胞系。我们的数据表明，GM-CSF发挥双重作用：它刺激细胞分裂，但同时上调Jak-Stat依赖性促凋亡蛋白。因此，AML中前半胱天冬酶水平的上调是持续生长刺激信号的一个标志。
