Departments of Stem Cell Transplantation and Cellular Therapy and Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4095, USA.
Clin Cancer Res. 2010 Mar 15;16(6):1865-74. doi: 10.1158/1078-0432.CCR-09-2551. Epub 2010 Mar 9.
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.
叉头转录因子（FOXO）是肿瘤抑制基因，可调节分化、代谢和细胞凋亡，其功能与信号转导途径相互作用，这些信号转导途径在急性髓细胞白血病（AML）中显示失调和具有预后意义。本研究评估了 AML 中 FOXO3A 总蛋白和磷酸化蛋白的表达水平及其与预后的相关性。
我们使用反相蛋白阵列方法测量了 511 例新诊断 AML 患者白血病富集蛋白样本中 FOXO3A 的总蛋白和磷酸化蛋白表达水平。
表达范围与正常 CD34+细胞相似，在血液和骨髓中相似。与诊断时相比，复发时总 FOXO3A 水平更高。pFOXO3A 或磷酸化与总蛋白（PT）的比值与核型无关，但在 FLT3 突变患者中更高。较高的 pFOXO3A 或 PT-FOXO3A 水平与更高的增殖相关，这表现为与更高的白细胞计数、骨髓百分比和血液原始细胞以及与更高水平的细胞周期蛋白 B1、D1 和 D3、pGSK3、pMTOR 和 pStat5 呈强相关性。pFOXO3A 或 PT-FOXO3A 水平较高的患者原发耐药率较高，缓解持续时间较短，这导致生存体验较差（P=0.0002）。这种影响独立于细胞遗传学。PT-FOXO3A 在多变量分析中是一个具有统计学意义的独立预测因子。
FOXO3A 的高磷酸化水平是 AML 中一种可治疗的、独立的不良预后因素。
