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The gene signature in CCAAT-enhancer-binding protein α dysfunctional acute myeloid leukemia predicts responsiveness to histone deacetylase inhibitors

机译:CCAAT-增强子结合蛋白α功能异常的急性髓细胞性白血病中的基因标志预测对组蛋白脱乙酰基酶抑制剂的反应

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textabstractC/EPBα proteins, encoded by the CCAAT-enhancer-binding protein α gene, play a crucial role in granulocytic development, and defects in this transcription factor have been reported in acute myeloid leukemia. Here, we defined the C/EBPα signature characterized by a set of genes up-regulated upon C/EBPα activation. We analyzed expression of the C/EBPα signature in a cohort of 525 patients with acute myeloid leukemia and identified a subset characterized by low expression of this signature. We referred to this group of patients as the C/EBPα dysfunctional subset. Remarkably, a large percentage of samples harboring C/EBPα biallelic mutations clustered within this subset. We hypothesize that re-activation of the C/EBPα signature in the C/EBPα dysfunctional subset could have therapeutic potential. In search for small molecules able to reverse the low expression of the C/EBPα signature we applied the connectivity map. This analysis predicted positive connectivity between the C/EBPα activation signature and histone deacetylase inhibitors. We showed that these inhibitors reactivate expression of the C/EBPα signature and promote granulocytic differentiation of primary samples from the C/EBPα dysfunctional subset harboring biallelic C/EBPα mutations. Altogether, our study identifies histone deacetylase inhibitors as potential candidates for the treatment of certain leukemias characterized by down-regulation of the C/EBPα signature.
机译:由CCAAT-增强子结合蛋白α基因编码的textabstractC /EPBα蛋白在粒细胞发育中起着至关重要的作用,并且在急性髓细胞性白血病中已经报道了该转录因子的缺陷。在这里,我们定义了以一组在C /EBPα激活后上调的基因为特征的C /EBPα签名。我们分析了525名急性髓性白血病患者队列中C /EBPα标记的表达,并鉴定了以该标记低表达为特征的亚群。我们将这组患者称为C /EBPα功能障碍的子集。值得注意的是,大部分带有C /EBPα双等位基因突变的样本都聚集在该子集中。我们假设C /EBPα功能异常亚群中C /EBPα标记的重新激活可能具有治疗潜力。为了寻找能够逆转C /EBPα标记的低表达的小分子,我们应用了连接图。该分析预测了C /EBPα激活信号和组蛋白脱乙酰基酶抑制剂之间的正连接性。我们表明,这些抑制剂可重新激活C /EBPα标记的表达,并促进来自具有双等位基因C /EBPα突变的C /EBPα功能障碍子集的主要样本的粒细胞分化。总而言之,我们的研究确定组蛋白脱乙酰基酶抑制剂是治疗某些以C /EBPα信号下调为特征的白血病的潜在候选药物。

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