Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia
Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia
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DOI：
10.1182/blood-2006-02-003475
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发表时间：
2006-10-01
期刊：
影响因子：
20.3
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
--
作者：
Kornblau, Steven M.;Womble, Matthew;Andreeff, Michael
信号转导途径（STP）的失调可能会通过赋予急性骨髓性白血病（AML）的细胞增殖和生存优势来促进白血病的发生。几种靶向STP的药物正在开发中;然而，STP之间的冗余和串扰可能会激活多个下游效应物，这可能会抵消单靶标抑制的效果。AML中多个STP同时激活的频率和AML中STP激活的预后相关性尚不清楚。STP蛋白表达（PKC α、ERK 2、pERK 2、AKT和pAKT）通过蛋白质印迹法在来自188名新诊断的未经治疗的AML患者的样本中测量。在单变量和多变量分析中，高水平的PKC α、ERK、pERK和pAKT，而不是AKT，是生存的不利因素，组合变量PKC α-ERK 2和pERK 2-pAKT也是如此。随着激活途径数量的增加，生存率逐渐降低。与基于单个通路激活频率预测的结果相比，患者更可能没有或所有3种通路都被激活，这强烈表明发生了交叉激活。多个STP的同时激活在AML中很常见，并且对预后具有进行性恶化的不良影响。因此，很可能只有靶向多重激活的STP的药物组合才对AML患者有益。
Deregulation of signal transduction pathways (STPs) may promote leukemogenesis by conferring cell proliferation and survival advantages in acute myelogenous leukemia (AML). Several agents targeting STPs are under development; however, redundancy and cross-talk between STPs could activate multiple downstream effectors and this could negate the effect of single-target inhibition. The frequency of concurrent activation of multiple STPs in AML and the prognostic relevance of STP activation in AML are unknown. STP protein expression (PKC alpha, ERK2, pERK2, AKT, and pAKT) was measured by Western blot in samples from 188 patients with newly diagnosed, untreated AML. In univariate and multivariate analysis high levels of PKC alpha, ERK, pERK, and pAKT, but not AKT, were adverse factors for survival as was the combination variable PKC alpha-ERK2&pERK2-pAKT. Survival progressively decreased as the number of activated pathways increased. Patients were more likely to have none or all 3 pathways activated than was predicted based on the frequency of individual pathway activation, strongly suggesting that cross-activation occurred. Simultaneous activation of multiple STPs is common in AML and has a progressively worse adverse effect on prognosis. It is thus likely that only combinations of agents that target the multiply activated STPs will be beneficial for patients with AML.