Highly phosphorylated FOXO3A is an adverse prognostic factor in acute myeloid leukemia.
Highly phosphorylated FOXO3A is an adverse prognostic factor in acute myeloid leukemia.
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DOI：
10.1158/1078-0432.ccr-09-2551
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发表时间：
2010-03-15
期刊：
影响因子：
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通讯作者：
Coombes KR
中科院分区：
文献类型：
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作者：
Kornblau SM;Singh N;Qiu Y;Chen W;Zhang N;Coombes KR
叉头转录因子（FOXO）是调节分化、代谢和凋亡的肿瘤抑制基因，其在功能上与信号转导通路相互作用，所述信号转导通路在急性髓细胞性白血病（AML）中显示出失调和预后。本研究评估了AML中FOXO 3A蛋白的表达水平和磷酸化的预后相关性。我们使用反相蛋白质阵列方法来测量511例新诊断的AML患者的白血病富集蛋白样本中FOXO 3A的总表达和磷蛋白表达水平。其表达范围与正常CD 34+细胞相似，在血液和骨髓中的表达范围相似。与诊断相比，复发时总FOXO 3A水平更高。pFOXO 3A水平或磷酸化与总磷酸化（PT）的比值与核型无关，但在FLT 3突变患者中较高。较高水平的pFOXO 3A或PT-FOXO 3A与增殖增加相关，这一点通过与较高的WBC、骨髓百分比和血胚细胞的强相关性以及与较高水平的细胞周期蛋白B1、D1和D3、pGSK 3、pMTOR和pStat 5的相关性得到证明。高水平pFOXO 3A或PT-FOXO 3A的患者原发性耐药率较高，缓解持续时间较短，联合收割机导致生存率较低（P = 0.0002）。这种效应与细胞遗传学无关。在多变量分析中，PT-FOXO 3A是一个具有统计学意义的独立预测因子。高水平的FOXO 3A磷酸化是AML中治疗靶向的、独立的不良预后因素。
The Forkhead transcription factors (FOXO) are tumor suppressor genes regulating differentiation, metabolism, and apoptosis that functionally interact with signal transduction pathways shown to be deregulated and prognostic in acute myelogenous leukemia (AML). This study evaluated the level of expression and the prognostic relevance of total and phosphorylated FOXO3A protein in AML. We used reverse-phase protein array methods to measure the level of total and phosphoprotein expression of FOXO3A, in leukemia-enriched protein samples from 511 newly diagnosed AML patients. The expression range was similar to normal CD34+ cells and similar in blood and marrow. Levels of total FOXO3A were higher at relapse compared with diagnosis. Levels of pFOXO3A or the ratio of phospho to total (PT) were not associated with karyotpe but were higher in patients with FLT3 mutations. Higher levels of pFOXO3A or PT-FOXO3A were associated with increased proliferation evidenced by strong correlation with higher WBC, percent marrow, and blood blasts and by correlation with higher levels of Cyclins B1, D1 and D3, pGSK3, pMTOR, and pStat5. Patients with High levels of pFOXO3A or PT-FOXO3A had higher rates of primary resistance and shorter remission durations, which combine to cause an inferior survival experience (P = 0.0002). This effect was independent of cytogenetics. PT-FOXO3A was a statistically significant independent predictor in multivariate analysis. High levels of phosphorylation of FOXO3A is a therapeutically targetable, independent adverse prognostic factor in AML.