Nilsson Helena Jernmark, Montano Giorgia, Ullmark Tove, Lennartsson Andreas, Drott Kristina, Järvstråt Linnea, Nilsson Björn, Vidovic Karina, Gullberg Urban
Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Oncotarget. 2017 Aug 3;8(50):87136-87150. doi: 10.18632/oncotarget.19896. eCollection 2017 Oct 20.
The Wilms' tumor gene 1 () is recurrently mutated in acute myeloid leukemia. Mutations and high expression of associate with a poor prognosis. In mice, WT1 cooperates with the () fusion gene in the induction of acute leukemia, further emphasizing a role for WT1 in leukemia development. Molecular mechanisms for WT1 are, however, incompletely understood. Here, we identify the transcriptional coregulator as a target gene of WT1. Analysis of gene expression profiles of leukemic samples revealed a positive correlation between the expression of and , as well as a non-zero partial correlation. Overexpression of in hematopoietic cells resulted in increased levels, while suppression of decreased expression. WT1 bound and transactivated the proximal promoter, as shown by ChIP and reporter experiments, respectively. ChIP experiments also revealed that WT1 can recruit NAB2 to the promoter, thus modulating the transcriptional activity of WT1, as shown by reporter experiments. Our results implicate as a previously unreported target gene of WT1 and that NAB2 acts as a transcriptional cofactor of WT1.
威尔姆斯瘤基因1(WT1)在急性髓系白血病中经常发生突变。WT1的突变和高表达与预后不良相关。在小鼠中,WT1与RUNX(RUNX)融合基因协同诱导急性白血病,进一步强调了WT1在白血病发生发展中的作用。然而,WT1的分子机制尚未完全阐明。在此,我们鉴定转录共调节因子NAB2为WT1的靶基因。对白血病样本基因表达谱的分析显示,NAB2与WT1的表达呈正相关,且存在非零偏相关。在造血细胞中过表达NAB2导致WTX水平升高,而抑制NAB2则降低WTX表达。染色质免疫沉淀(ChIP)和报告基因实验分别表明,WT1结合并反式激活WTX近端启动子。ChIP实验还显示,WT1可将NAB2募集至WTX启动子,报告基因实验表明,这可调节WT1的转录活性。我们的结果表明,NAB2是WT1一个此前未报道的靶基因,且NAB2作为WT1的转录辅因子发挥作用。