Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations
Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations
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DOI：
10.3324/haematol.2013.095604
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发表时间：
2014-05-01
期刊：
影响因子：
10.1
通讯作者：
Valk, Peter J. M.
中科院分区：
文献类型：
--
作者：
Abbas, Saman;Sanders, Mathijs A.;Valk, Peter J. M.
急性髓系白血病是一种以反复发生的分子异常为特征的肿瘤，传统上通过细胞遗传学分析来证实。我们使用高密度全基因组基因分型和基因表达谱来揭示急性髓系白血病获得性隐匿性异常。通过对137例原发急性髓系白血病患者进行全基因组基因分型，发现2例患者在14q32号染色体上出现反复的局域扩增，其中包括基因BCL11B、CCNK、C14orf177和SETD3。在受影响的病例中，BCL11B基因显示出持续的高mRNA表达，而其他基因的表达没有受到干扰。荧光原位杂交法检测40例bcl11b高表达的急性髓系白血病[高于中位数2.5倍，40例(7.5%)]，另有2例出现14q32异常。在4例BCL11B重排的病例中，14q32基因座与不同的配对染色体融合。事实上，在两个案例中，我们证明了焦点14q32扩增整合到转录活性位点。涉及BCL11B的易位导致全长BCL11B蛋白表达增加。BCL11B重排的急性髓系白血病同时表达髓系标志和T细胞标志。这些双表型急性白血病都携带Flt3内部串联复制，这是急性髓系白血病的特征标志。BCL11B基因在急性髓系白血病中的表达与其他T细胞特异性基因的表达密切相关。异位表达Bcl11b的髓样32D(GCSF-R)细胞增殖速度减慢，成熟程度降低。总之，通过高通量全基因组基因分型和基因表达谱分析的综合方法，我们确定BCL11B是急性髓系白血病的候选癌基因。
Acute myeloid leukemia is a neoplasm characterized by recurrent molecular aberrations traditionally demonstrated by cytogenetic analyses. We used high density genome-wide genotyping and gene expression profiling to reveal acquired cryptic abnormalities in acute myeloid leukemia. By genome-wide genotyping of 137 cases of primary acute myeloid leukemia, we disclosed a recurrent focal amplification on chromosome 14q32, which included the genes BCL11B, CCNK, C14orf177 and SETD3, in two cases. In the affected cases, the BCL11B gene showed consistently high mRNA expression, whereas the expression of the other genes was unperturbed. Fluorescence in situ hybridization on 40 cases of acute myeloid leukemia with high BCL11B mRNA expression [ 2.5-fold above median; 40 out of 530 cases (7.5%)] revealed 14q32 abnormalities in two additional cases. In the four BCL11B-rearranged cases the 14q32 locus was fused to different partner chromosomes. In fact, in two cases, we demonstrated that the focal 14q32 amplifications were integrated into transcriptionally active loci. The translocations involving BCL11B result in increased expression of full-length BCL11B protein. The BCL11B-rearranged acute myeloid leukemias expressed both myeloid and T-cell markers. These biphenotypic acute leukemias all carried FLT3 internal tandem duplications, a characteristic marker of acute myeloid leukemia. BCL11B mRNA expression in acute myeloid leukemia appeared to be strongly associated with expression of other T-cell-specific genes. Myeloid 32D(GCSF-R) cells ectopically expressing Bcl11b showed decreased proliferation rate and less maturation. In conclusion, by an integrated approach involving high-throughput genome-wide genotyping and gene expression profiling we identified BCL11B as a candidate oncogene in acute myeloid leukemia.