WT1招募TET2来调节其靶基因表达并抑制白血病细胞增殖。
WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation.
作者信息
Wang Yiping, Xiao Mengtao, Chen Xiufei, Chen Leilei, Xu Yanping, Lv Lei, Wang Pu, Yang Hui, Ma Shenghong, Lin Huaipeng, Jiao Bo, Ren Ruibao, Ye Dan, Guan Kun-Liang, Xiong Yue
机构信息
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
出版信息
Mol Cell. 2015 Feb 19;57(4):662-673. doi: 10.1016/j.molcel.2014.12.023. Epub 2015 Jan 15.
The TET2 DNA dioxygenase regulates cell identity and suppresses tumorigenesis by modulating DNA methylation and expression of a large number of genes. How TET2, like most other chromatin-modifying enzymes, is recruited to specific genomic sites is unknown. Here we report that WT1, a sequence-specific transcription factor, is mutated in a mutually exclusive manner with TET2, IDH1, and IDH2 in acute myeloid leukemia (AML). WT1 physically interacts with and recruits TET2 to its target genes to activate their expression. The interaction between WT1 and TET2 is disrupted by multiple AML-derived TET2 mutations. TET2 suppresses leukemia cell proliferation and colony formation in a manner dependent on WT1. These results provide a mechanism for targeting TET2 to a specific DNA sequence in the genome. Our results also provide an explanation for the mutual exclusivity of WT1 and TET2 mutations in AML, and suggest an IDH1/2-TET2-WT1 pathway in suppressing AML.
TET2 DNA双加氧酶通过调节DNA甲基化和大量基因的表达来调控细胞特性并抑制肿瘤发生。与大多数其他染色质修饰酶一样，TET2如何被招募至特定基因组位点尚不清楚。在此，我们报告称，在急性髓系白血病（AML）中，序列特异性转录因子WT1与TET2、异柠檬酸脱氢酶1（IDH1）和异柠檬酸脱氢酶2（IDH2）以互斥方式发生突变。WT1与TET2发生物理相互作用，并将TET2招募至其靶基因以激活它们的表达。WT1与TET2之间的相互作用被多种AML来源的TET2突变破坏。TET2以依赖WT1的方式抑制白血病细胞增殖和集落形成。这些结果提供了一种将TET2靶向基因组中特定DNA序列的机制。我们的结果还解释了AML中WT1和TET2突变的互斥性，并提示了一条抑制AML的IDH1/2-TET2-WT1通路。
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