WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation

By Yiping Wang, Mengtao Xiao, Xiufei Chen, Lei-lei Chen, Yan-ping Xu, Lei Lv, Pu Wang, Hui Yang, Shenghong Ma, Huaipeng Lin and 5 more. 2015

289 citations recorded by the source corpus.

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 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.

Subfields: Hematology, Molecular Biology

Citations in the corpus

• Impact of cytosine methylation on DNA binding specificities of human transcription factors (2017, neutral): “These results are consistent with the earlier finding that TF binding induces loss of local DNAmethylation, potentially using the TET/TDGdependent demethylation pathway (7, 49, 50).”