Early B-cell factor-associated zinc-finger gene is a frequent target of retroviral integration in murine B-cell lymphomas
Early B-cell factor-associated zinc-finger gene is a frequent target of retroviral integration in murine B-cell lymphomas
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DOI：
10.1038/sj.onc.1207452
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发表时间：
2004-04-08
期刊：
影响因子：
8
通讯作者：
Copeland, NG
中科院分区：
文献类型：
--
作者：
Warming, S;Suzuki, T;Copeland, NG
早期B细胞因子（EBF）相关锌指蛋白（EBFAZ）结合并负调节EBF，EBF是B细胞谱系定型和嗅觉上皮发育所需的碱性螺旋-环-螺旋转录因子。它还响应骨形态发生蛋白2（BMP 2）信号传导，与SMA和MAD相关蛋白1（SMAD 1）和SMAD 4结合。它与亲嗜性病毒整合位点3（EVI 3）高度相关，EVI 3是一种与EBFAZ一样含有30个Kruppel样锌指重复序列的蛋白质。在以前的研究中，我们发现Evi 3是AKXD 27 B细胞淋巴瘤中逆转录病毒整合的常见靶标。在这里，我们表明EBFAZ也是一个常见的目标。Ebfaz和Evi 3的整合是相互排斥的，这表明它们在相同的肿瘤途径中发挥作用。在Ebfaz或Evi 3整合的淋巴瘤表达前B细胞特异性标记免疫球蛋白λ链5，并含有免疫球蛋白重链重排，表明它们在早期B细胞阶段被阻断。与Evi 3（其在正常B细胞中以低水平表达）或Ebfaz（其在B细胞中不表达）不同，这两种基因在病毒整合后高度表达。总的来说，我们的结果表明Ebfaz的异位表达可以替代B细胞疾病中Evi 3的上调表达，并强调了该基因家族在造血系统癌症中的重要性。
The early B-cell factor (EBF)-associated zinc-finger protein (EBFAZ) binds to and negatively regulates EBF, a basic helix-loop-helix transcription factor required for B-cell lineage commitment and development of the olfactory epithelium. It also binds to SMA- and MAD-related protein 1 (SMAD1) and SMAD4 in response to bone morphogenic protein 2 (BMP2) signaling. It is highly related to ecotropic viral integration site 3 (EVI3), a protein that, like EBFAZ, contains 30 Kruppel-like zinc finger repeats. In previous studies, we showed that Evi3 is a frequent target of retroviral integration in AKXD27 B-cell lymphomas. Here, we show that EBFAZ is also a frequent target. Integrations at Ebfaz and Evi3 are mutually exclusive, suggesting that they function in the same tumor pathway. Lymphomas with integrations at Ebfaz or Evi3 express the pre-B-cell-specific marker immunoglobulin lambda chain 5, and contain immunoglobulin heavy-chain rearrangements, suggesting that they are blocked at an early B-cell stage. Unlike Evi3, which is expressed at low levels in normal B cells, or Ebfaz, which is not expressed in B cells, both genes are highly expressed following viral integration. Collectively, our results suggest that ectopic expression of Ebfaz can substitute for the upregulated expression of Evi3 in B-cell disease and highlight the importance of this gene family in hematopoietic cancer.