An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML
An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML
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DOI：
10.1182/blood-2007-09-115055
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发表时间：
2008-05-01
期刊：
影响因子：
20.3
通讯作者：
Pollack, Jonathan R.
中科院分区：
文献类型：
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作者：
Bullinger, Lars;Doehner, Konstanze;Pollack, Jonathan R.
核型正常的急性髓性白血病（NK-AML）是一种预后中等但分子和临床异质性很大的细胞遗传学分组。在该亚组中，FLT 3（FMS样酪氨酸激酶3）内部串联重复（ITD）突变的存在预测不太有利的结果。我们研究的目的是发现与FLT 3-ITD突变相关的基因表达模式，并评估FLT 3标签用于突变鉴定的实用性。使用DNA微阵列分析65例NK-AML病例的训练集中的基因表达，并使用微阵列预测分析方法进行监督分析，以建立基于基因表达的FLT 3-ITD突变状态预测因子。由20个基因组成的最佳预测因子，然后通过对来自72个NK-AML病例的独立测试集的表达谱进行分类来评估。预测因子在分类FLT 3-ITD状态方面表现出中等性能（73%灵敏度; 85%特异性）。然而，值得注意的是，在预测临床结果方面，签名优于FLT 3-ITD突变状态。特征可以更好地定义临床相关的FLT 3信号传导和/或表型FLT 3-ITD的替代变化，而特征基因提供了剖析这些途径的起点。我们的研究结果支持了基于基因表达的FLT 3途径激活测量在AML中的潜在临床实用性。
Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation and to evaluate the utility of a FLT3 signature for prognostication. DNA microarrays were used to profile gene expression in a training set of 65 NK-AML cases, and supervised analysis, using the Prediction Analysis of Microarrays method, was applied to build a gene expression-based predictor of FLT3-ITD mutation status. The optimal predictor, composed of 20 genes, was then evaluated by classifying expression profiles from an independent test set of 72 NK-AML cases. The predictor exhibited modest performance (73% sensitivity; 85% specificity) in classifying FLT3-ITD status. Remarkably, however, the signature outperformed FLT3-ITD mutation status in predicting clinical outcome. The signature may better define clinically relevant FLT3 signaling and/or alternative changes that phenocopy FLT3-ITD, whereas the signature genes provide a starting point to dissect these pathways. Our findings support the potential clinical utility of a gene expression-based measure of FLT3 pathway activation in AML.