Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency
Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency
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DOI：
10.1182/blood-2014-12-617282
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发表时间：
2015-06-25
期刊：
影响因子：
20.3
通讯作者：
Sigvardsson, Mikael
中科院分区：
文献类型：
--
作者：
Prasad, Mahadesh A. J.;Ungerback, Jonas;Sigvardsson, Mikael
早期b细胞因子1 （Ebf1）是一种在正常和恶性b淋巴细胞发育中具有剂量依赖性功能的转录因子。为了进一步了解Ebf1在恶性转化中的作用，我们研究了功能性Ebf1剂量降低对小鼠b细胞祖细胞的影响。基因表达分析表明，Ebf1参与DNA修复和细胞存活重要基因的调控。对稳态DNA损伤和紫外光诱导DNA损伤后的研究证实，缺乏Ebf1 1个功能等位基因的前b细胞显示出DNA损伤增加的迹象。这与包括Rad51在内的DNA修复基因的表达减少有关，染色质免疫沉淀数据表明Rad51是Ebf1的直接靶点。虽然减少Ebf1的剂量并没有显著增加小鼠的肿瘤形成，但在Ebf1和Pax5基因杂合突变的小鼠中，观察到前b细胞白血病的频率急剧增加，揭示了这些蛋白的联合剂量减少的协同作用。我们的数据表明，Ebf1以剂量依赖的方式控制DNA修复，这可能解释了Ebf1基因丢失在人类白血病中的频繁参与。
Early B-cell factor 1 (Ebf1) is a transcription factor with documented dose-dependent functions in normal and malignant B-lymphocyte development. To understand more about the roles of Ebf1 in malignant transformation, we investigated the impact of reduced functional Ebf1 dosage on mouse B-cell progenitors. Gene expression analysis suggested that Ebf1 was involved in the regulation of genes important for DNA repair and cell survival. Investigation of the DNA damage in steady state, as well as after induction of DNA damage by UV light, confirmed that pro-B cells lacking 1 functional allele of Ebf1 display signs of increased DNA damage. This correlated to reduced expression of DNA repair genes including Rad51, and chromatin immunoprecipitation data suggested that Rad51 is a direct target for Ebf1. Although reduced dosage of Ebf1 did not significantly increase tumor formation in mice, a dramatic increase in the frequency of pro-B cell leukemia was observed in mice with combined heterozygous mutations in the Ebf1 and Pax5 genes, revealing a synergistic effect of combined dose reduction of these proteins. Our data suggest that Ebf1 controls DNA repair in a dose-dependent manner providing a possible explanation to the frequent involvement of EBF1 gene loss in human leukemia.