Warming Søren, Suzuki Takeshi, Yamaguchi Terry P, Jenkins Nancy A, Copeland Neal G
Mouse Cancer Genetics Program, National Cancer Institute, Center for Cancer Research, West 7th Street at Fort Detrick, Frederick, MD 21702, USA.
Oncogene. 2004 Apr 8;23(15):2727-31. doi: 10.1038/sj.onc.1207452.
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 Krüppel-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.
早期B细胞因子（EBF）相关锌指蛋白（EBFAZ）与EBF结合并对其起负调控作用，EBF是一种碱性螺旋-环-螺旋转录因子，对于B细胞谱系定向分化和嗅觉上皮发育是必需的。它还能响应骨形态发生蛋白2（BMP2）信号，与SMA和MAD相关蛋白1（SMAD1）及SMAD4结合。它与亲嗜性病毒整合位点3（EVI3）高度相关，EVI3是一种蛋白质，和EBFAZ一样，含有30个Krüppel样锌指重复序列。在先前的研究中，我们发现Evi3是AKXD27 B细胞淋巴瘤中逆转录病毒整合的常见靶点。在此，我们表明EBFAZ也是常见靶点。Ebfaz和Evi3处的整合相互排斥，这表明它们在同一肿瘤通路中发挥作用。在Ebfaz或Evi3处有整合的淋巴瘤表达前B细胞特异性标志物免疫球蛋白λ链5，并含有免疫球蛋白重链重排，这表明它们在早期B细胞阶段受阻。与在正常B细胞中低水平表达的Evi3或在B细胞中不表达的Ebfaz不同，这两个基因在病毒整合后均高度表达。总体而言，我们的结果表明，Ebfaz的异位表达可替代B细胞疾病中Evi3上调的表达，并突出了该基因家族在造血系统癌症中的重要性。
