Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1
Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1
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DOI：
10.1182/blood-2007-02-073486
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发表时间：
2007-11-15
期刊：
影响因子：
20.3
通讯作者：
Delwel, Ruud
中科院分区：
文献类型：
--
作者：
Wouters, Bas J.;Jorda, Meritxell Alberich;Delwel, Ruud
急性髓性白血病（AML）的基因表达谱允许发现以前未被识别的分子实体。在这里，我们确定了一个特定的AML亚组，由表达式定义。与髓系转录因子CCAAT/增强子结合蛋白α（C/EBP α）突变的AML相似，但缺乏此类突变。我们发现在这些白血病中，CEBPA基因被沉默，这与频繁的启动子超甲基化有关。白血病表型显示T细胞基因的异常表达，其中CD 7最为一致。我们确定了2种可能导致这种表型的机制。首先，Cebpa的缺乏导致从条件性Cebpa敲除小鼠分离的造血干细胞中特异性T细胞转录物（即Cd 7和Lck）的上调。第二，TRIB 2的表达增强，我们在这里将其确定为T细胞定型因子NOTCH 1的直接靶点，表明异常激活的Notch信号传导。在新鉴定的亚组的几个标本中发现了脓疱激活NOTCH 1突变，而大量对照AML为突变阴性。基因表达预测特征允许在独立的AML系列中检测类似的白血病病例。
Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression. profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBP alpha), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hyper-methylation. The leukemias phenotypically showed aberrant expression of Tcell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hemaopoitic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML.