Laricchia-Robbio Leopoldo, Premanand Kavitha, Rinaldi Ciro R, Nucifora Giuseppina
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Cancer Res. 2009 Feb 15;69(4):1633-42. doi: 10.1158/0008-5472.CAN-08-2562. Epub 2009 Feb 10.
EVI1 is an oncogene inappropriately expressed in the bone marrow (BM) of approximately 10% of myelodysplastic syndrome (MDS) patients. This disease is characterized by severe anemia and multilineage myeloid dysplasia that are thought to be a major cause of mortality in MDS patients. We earlier reported on a mouse model that constitutive expression of EVI1 in the BM led to fatal anemia and myeloid dysplasia, as observed in MDS patients, and we subsequently showed that EVI1 interaction with GATA1 blocks proper erythropoiesis. Whereas this interaction could provide the basis for the erythroid defects in EVI1-positive MDS, it does not explain the alteration of myeloid differentiation. Here, we have examined the expression of several genes activated during terminal myelopoiesis in BM cells and identified a group of them that are altered by EVI1. A common feature of these genes is their regulation by the transcription factor PU.1. We report here that EVI1 interacts with PU.1 and represses the PU.1-dependent activation of a myeloid promoter. EVI1 does not seem to inhibit PU.1 binding to DNA, but rather to block its association with the coactivator c-Jun. After mapping the PU.1-EVI1 interaction sites, we show that an EVI1 point mutant, unable to bind PU.1, restores the activation of PU.1-regulated genes and allows a normal differentiation of BM progenitors in vitro.
EVI1是一种癌基因，在约10%的骨髓增生异常综合征（MDS）患者的骨髓（BM）中异常表达。这种疾病的特征是严重贫血和多系髓系发育异常，被认为是MDS患者死亡的主要原因。我们之前报道了一个小鼠模型，在该模型中，BM中EVI1的组成型表达导致了如MDS患者中所观察到的致命性贫血和髓系发育异常，随后我们发现EVI1与GATA1的相互作用会阻碍正常的红细胞生成。虽然这种相互作用可能为EVI1阳性MDS中的红系缺陷提供了基础，但它并不能解释髓系分化的改变。在这里，我们检测了BM细胞终末髓系生成过程中几个被激活基因的表达，并鉴定出其中一组基因被EVI1改变。这些基因的一个共同特征是它们受转录因子PU.1的调控。我们在此报告，EVI1与PU.1相互作用并抑制髓系启动子的PU.1依赖性激活。EVI1似乎并不抑制PU.1与DNA的结合，而是阻断其与共激活因子c-Jun的结合。在定位了PU.1-EVI1相互作用位点后，我们表明一个无法结合PU.1的EVI1点突变体可恢复PU.1调控基因的激活，并使BM祖细胞在体外正常分化。
