Transcriptional deregulation of homeobox gene ZHX2 in Hodgkin lymphoma
Transcriptional deregulation of homeobox gene ZHX2 in Hodgkin lymphoma
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DOI：
10.1016/j.leukres.2011.10.019
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发表时间：
2012-05-01
影响因子：
2.7
通讯作者：
MacLeod, Roderick A. F.
中科院分区：
文献类型：
--
作者：
Nagel, Stefan;Schneider, Bjoern;MacLeod, Roderick A. F.
最近，我们在霍奇金淋巴瘤（HL）中发现了一种新的染色体重排，t(4;8)(q27;q24)，其目标是位于复发断点8q24的同源盒基因ZHX2。这种畸变删除了ZHX2的远上游区域，导致沉默转录精确定位激活元件的丢失。在这里，我们在这个缺失区域寻找潜在的结合位点来分析这个肿瘤抑制基因在b细胞恶性肿瘤中的转录失调。sirna介导的敲低和报告基因分析发现同源结构域蛋白MSX1和bZIP蛋白XBP1两个转录因子直接调控ZHX2的表达。此外，msx1辅助因子组蛋白H1C介导ZHX2的抑制，并在L-1236细胞株中表达水平增强。荧光原位杂交和基因组阵列分析表明，在一些HL细胞系中，MSX1在4p16和H1C在6p22的基因位点发生了重排，这与它们的表达活性改变有关。与原代造血细胞相比，6/7 HL细胞系中XBP1的表达降低。综上所述，我们的研究结果证明了降低肿瘤抑制基因ZHX2在HL细胞系中的表达的多种机制：增强结合位点的缺失，激活因子MSX1和XBP1的表达减少，以及MSX1辅抑制因子H1C的过表达。此外，参与该调节网络的基因的染色体失调突出了它们在b细胞发育和恶性肿瘤中的作用。(C) 2011 Elsevier Ltd.版权所有。
Recently, we identified a novel chromosomal rearrangement in Hodgkin lymphoma (HL), t(4;8)(q27;q24), which targets homeobox gene ZHX2 at the recurrent breakpoint 8q24. This aberration deletes the far upstream region of ZHX2 and results in silenced transcription pinpointing loss of activatory elements. Here, we have looked for potential binding sites within this deleted region to analyze the transcriptional deregulation of this tumor suppressor gene in B-cell malignancies. SiRNA-mediated knockdown and reporter gene analyses identified two transcription factors, homeodomain protein MSX1 and bZIP protein XBP1, directly regulating ZHX2 expression. Furthermore, MSX1-cofactor histone H1C mediated repression of ZHX2 and showed enhanced expression levels in cell line L-1236. As demonstrated by fluorescence in situ hybridization and genomic array analysis, the gene loci of MSX1 at 4p16 and H1C at 6p22 were rearranged in several HL cell lines, correlating with their altered expression activity. The expression of XBP1 was reduced in 6/7 HL cell lines as compared to primary hematopoietic cells. Taken together, our results demonstrate multiple mechanisms decreasing expression of tumor suppressor gene ZHX2 in HL cell lines: loss of enhancing binding sites, reduced expression of activators MSX1 and XBP1, and overexpression of MSX1-corepressor H1C. Moreover, chromosomal deregulations of genes involved in this regulative network highlight their role in development and malignancy of B-cells. (C) 2011 Elsevier Ltd. All rights reserved.