Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia
Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia
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DOI：
10.1016/s1535-6108(02)00018-1
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发表时间：
2002-02-01
期刊：
影响因子：
50.3
通讯作者：
Look, AT
中科院分区：
文献类型：
--
作者：
Ferrando, AA;Neuberg, DS;Look, AT
人类T细胞白血病可由涉及T细胞受体基因的特定染色体易位激活的癌基因引起。在这里，我们表明，五种不同的T细胞癌基因（HOX 11，TAL 1，LYL 1，LMO 1和LMO 2）往往异常表达的情况下，染色体异常。利用寡核苷酸微阵列，我们鉴定了几个在正常胸腺细胞发育的特定阶段指示白血病停滞的基因表达特征：LYL 1（+）特征（pro-T），HOX 11（+）（早期皮质胸腺细胞）和TAL 1（+）（晚期皮质胸腺细胞）。基因表达特征的分层聚类分析根据其共享的致癌途径对样本进行分组，并将HOX 11 L2激活确定为T细胞白血病发生中的新事件。这些发现具有临床重要性，因为HOX 11活化与良好的预后显著相关，而TAL 1、LYL 1或令人惊讶的HOX 11 L2的表达赋予对治疗的差得多的反应。我们的研究结果说明了基因表达谱的力量，以阐明相关的人类白血病的转化途径。
Human T cell leukemias can arise from oncogenes activated by specific chromosomal translocations involving the T cell receptor genes. Here we show that five different T cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, we identified several gene expression signatures that were indicative of leukemic arrest at specific stages of normal thymocyte development: LYL1(+) signature (pro-T), HOX11(+) (early cortical thymocyte), and TAL1(+) (late cortical thymocyte). Hierarchical clustering analysis of gene expression signatures grouped samples according to their shared oncogenic pathways and identified HOX11L2 activation as a novel event in T cell leukemogenesis. These findings have clinical importance, since HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1, or, surprisingly, HOX11L2 confers a much worse response to treatment. Our results illustrate the power of gene expression profiles to elucidate transformation pathways relevant to human leukemia.