title: WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation.
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.
authors.affiliation: 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.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Mengtao
authors.initials: M
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Xiufei
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Leilei
authors.initials: L
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Lv
authors.affiliation: 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.
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Huaipeng
authors.initials: H
authors.lastname: Lin
authors.affiliation: Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiao
authors.affiliation: Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Ruibao
authors.initials: R
authors.lastname: Ren
authors.affiliation: 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.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049308:Dioxygenases; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D011518:Proto-Oncogene Proteins; D025721:WT1 Proteins; C583751:WT1 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human