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Mol Cell. 2015 Feb 19;57(4):662-673. doi: 10.1016/j.molcel.2014.12.023. Epub 2015 Jan 15.

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

Author information

1
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.
2
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.
3
Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
4
Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
5
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. Electronic address: yedan@fudan.edu.cn.
6
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.
7
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. Electronic address: yxiong@email.unc.edu.

Abstract

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.

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PMID:
25601757
PMCID:
PMC4336627
DOI:
10.1016/j.molcel.2014.12.023
[Indexed for MEDLINE]
Free PMC Article

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