Activation of the RAS pathway is predictive for a chemosensitive phenotype of acute myelogenous leukemia blasts
Activation of the RAS pathway is predictive for a chemosensitive phenotype of acute myelogenous leukemia blasts
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DOI：
10.1158/1078-0432.ccr-04-2232
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发表时间：
2005-05-01
影响因子：
11.5
通讯作者：
Schaich, M
中科院分区：
文献类型：
--
作者：
Illmer, T;Thiede, C;Schaich, M
目的：RAS通路的激活在癌细胞中起着重要作用。在急性髓性白血病（AML）中，RAS基因的突变导致该途径的内在激活。到目前为止，临床研究无法找到RAS突变与AML治疗后临床结局的明确关联。这可能是由于RAS通路激活的替代起始事件，如组成型酪氨酸激酶激活或Ras调节基因突变。（126个作为训练群体，65个作为测试群体）用谷胱甘肽S-转移酶下拉测定法使用活化Ras的Raf结合来研究Ras活性。AML样本显示出广泛的Ras活性值，这与正常骨髓供体形成对比，正常骨髓供体显示出没有或非常有限的Ras活性。使用基于半定量Western印迹的Ras结合评分，我们定义了具有强Ras活性的患者，并将Ras活性与RAS突变进行比较。令人惊讶的是，只有少数RAS突变的AML样本（22.2%）显示出强Ras活性，而25例患者在没有RAS突变的情况下表现出强Ras活性。根据RAS突变，临床结局未显示差异。与此相反，Ras活性预测高反应率（P < 0.05），并证明是一个独立的因素，总生存率（P < 0.05）在年轻AML患者接受高剂量1-β-D-阿拉伯呋喃胞嘧啶作为诱导therapy.Conclusion：数据突出的作用Ras激活的替代途径没有RAS突变。内源性激活的Ras似乎增加了AML母细胞对高剂量1-β-D-阿拉伯呋喃糖基胞嘧啶治疗的敏感性。
Purpose: Activation of the RAS pathway plays a major role in cancer cells. In acute myeloid leukemia (AML), mutations of the RAS genes cause an intrinsic activation of this pathway. Until now, clinical studies could not find clear association of RAS mutations with the clinical outcome after AML therapy. This could be due to alternative initiating events for activation of the RAS pathway like constitutive tyrosine kinase activation or mutations in Ras-regulating genes.Experimental Design: In total, 191 AML patients (126 as training population and 65 as test population) were studied for Ras activity with a glutathione S-transferase pull-down assay using Raf binding of activated Ras.Results: AML samples showed a wide range of Ras activity values, which was in contrast to normal bone marrow donors who showed no or very limited Ras activity. Using a Ras binding score based on semiquantitative Western blotting, we defined patients with strong Ras activity and compared Ras activity with RAS mutation. Surprisingly, only a minority of RAS mutated AML samples (22.2%) showed strong Ras activity, whereas 25 patients presented strong Ras activity in the absence of RAS mutations. Clinical outcome did not show differences according to RAS mutations. In contrast, Ras activity predicted for a high response rate (P < 0.05) and proved to be an independent factor for overall survival rate (P < 0.05) in younger AML patients receiving high-dose 1-beta-D-arabinofuranosylcytosine as induction therapy.Conclusion: The data highlight the role for alternative pathways of Ras activation without RAS mutations. Intrinsically activated Ras seems to increase sensitivity of the AML blast to high-dose 1-beta-D-arabinofuranosylcytosine therapy.