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Cell Rep. 2014 Dec 11;9(5):1841-55. 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

  • 1Human 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.
  • 2Department 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.
  • 3Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
  • 4Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • 5Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA.
  • 6Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • 7Department of Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
  • 8Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
  • 9Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • 10Promega Corporation, Madison, WI 53703, USA.
  • 11Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
  • 12Department of Pathology, New York University Cancer Institute, New York, NY 10016, USA.
  • 13Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium.
  • 14Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • 15Department of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
  • 16Montefiore Medical Center, New York, NY 10466, USA.
  • 17Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 18Department 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.
  • 19Section 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.
  • 20Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: amm2014@med.cornell.edu.
  • 21Department 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.
  • 22Human 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.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

PMID:
25482556
[PubMed - indexed for MEDLINE]
PMCID:
PMC4267494
Free PMC Article

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