The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children
The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children
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DOI：
10.1182/blood-2006-12-064683
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发表时间：
2007-08-15
期刊：
影响因子：
20.3
通讯作者：
Soulier, Jean
中科院分区：
文献类型：
--
作者：
Clappier, Emmanuelle;Cuccuini, Wendy;Soulier, Jean
C-Myb转录因子对造血至关重要，包括在t细胞谱系中。C-Myb基因座是逆转录病毒插入突变的常见位点，但在人类恶性肿瘤中没有复发性基因组参与的报道。在这里，我们鉴定了人类t细胞急性白血病（T-ALL）中涉及C-MYB位点6q23的2种类型的基因组改变。首先，我们发现TCRB和C-MYB位点并置的反向易位t(6;7)(q23;q34) （n = 6例）。其次，通过基于阵列的比较基因组杂交（array-CGH）进行全基因组拷贝数分析，确定了包括C-MYB在内的短体细胞复制（MYBdup, n = 13例84 T-ALL， 15%）。包括等位基因特异性方法在内的表达分析显示，与其他t - all相比，myb重排病例中的C-MYB表达更强，而TCRB-MYB病例中的C-MYB等位基因表达明显偏转，这表明易位驱动的失调表达可能克服了细胞下调C-MYB的企图。引人注目的是，通过临床、基因组和大规模基因表达分析对T-ALL进行的分析表明，TCRB-MYB易位定义了一种新的T-ALL亚型，这种亚型与t细胞白血病的发病年龄非常小（中位数为2.2岁）和增殖/有丝分裂表达特征相关。相比之下，MYBdup改变与先前定义的T-ALL亚型相关。
The C-Myb transcription factor is essential for hematopoiesis, including in the T-cell lineage. The C-Myb locus is a common site of retroviral insertional mutagenesis, however no recurrent genomic involvement has been reported in human malignancies. Here, we identified 2 types of genomic alterations involving the C-MYB locus at 6q23 in human T-cell acute leukemia (T-ALL). First, we found a reciprocal translocation, t(6;7)(q23;q34), that juxtaposed the TCRB and C-MYB loci (n = 6 cases). Second, a genome-wide copy-number analysis by array-based comparative genomic hybridization (array-CGH) identified short somatic duplications that include C-MYB (MYBdup, n = 13 cases of 84 T-ALL, 15%). Expression analysis, including allele-specific approaches, showed stronger C-MYB expression in the MYB-rearranged cases compared with other T-ALLs, and a dramatically skewed C-MYB allele expression in the TCRB-MYB cases, which suggests that a translocation-driven deregulated expression may overcome a cellular attempt to down- regulate C-MYB. Strikingly, profiling of the T-ALLs by clinical, genomic, and large-scale gene expression analyses shows that the TCRB-MYB translocation defines a new T-ALL subtype associated with a very young age for T-cell leukemia (median, 2.2 years) and with a proliferation/mitosis expression signature. By contrast, the MYBdup alteration was associated with the previously defined T-ALL subtypes.