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Cell Rep. 2014 Dec 11;9(5):1841-1855. doi: 10.1016/j.celrep.2014.11.004. Epub 2014 Dec 4.

DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA; Berlin Institute for Medical Systems Biology, Max Delbrück Centre for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
3
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
5
Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA.
6
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
7
Department of Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
8
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
9
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
10
Promega Corporation, Madison, WI 53703, USA.
11
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
12
Department of Pathology, New York University Cancer Institute, New York, NY 10016, USA.
13
Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium.
14
Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
15
Department of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
16
Montefiore Medical Center, New York, NY 10466, USA.
17
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
18
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA; The Feil Family Brain and Mind Research Institute, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address: chm2042@med.cornell.edu.
19
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; The University of Chicago Comprehensive Cancer Research Center, Chicago, IL 60637, USA. Electronic address: lgodley@medicine.bsd.uchicago.edu.
20
Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: amm2014@med.cornell.edu.
21
Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: marfigue@med.umich.edu.
22
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: leviner@mskcc.org.

Abstract

Somatic mutations in IDH1/IDH2 and TET2 result in impaired TET2-mediated conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The observation that WT1 inactivating mutations anticorrelate with TET2/IDH1/IDH2 mutations in acute myeloid leukemia (AML) led us to hypothesize that WT1 mutations may impact TET2 function. WT1 mutant AML patients have reduced 5hmC levels similar to TET2/IDH1/IDH2 mutant AML. These mutations are characterized by convergent, site-specific alterations in DNA hydroxymethylation, which drive differential gene expression more than alterations in DNA promoter methylation. WT1 overexpression increases global levels of 5hmC, and WT1 silencing reduced 5hmC levels. WT1 physically interacts with TET2 and TET3, and WT1 loss of function results in a similar hematopoietic differentiation phenotype as observed with TET2 deficiency. These data provide a role for WT1 in regulating DNA hydroxymethylation and suggest that TET2 IDH1/IDH2 and WT1 mutations define an AML subtype defined by dysregulated DNA hydroxymethylation.

PMID:
25482556
PMCID:
PMC4267494
DOI:
10.1016/j.celrep.2014.11.004
[Indexed for MEDLINE]
Free PMC Article

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