Cell Reports (Dec 2014)
DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia
- Raajit Rampal,
- Altuna Alkalin,
- Jozef Madzo,
- Aparna Vasanthakumar,
- Elodie Pronier,
- Jay Patel,
- Yushan Li,
- Jihae Ahn,
- Omar Abdel-Wahab,
- Alan Shih,
- Chao Lu,
- Patrick S. Ward,
- Jennifer J. Tsai,
- Todd Hricik,
- Valeria Tosello,
- Jacob E. Tallman,
- Xinyang Zhao,
- Danette Daniels,
- Qing Dai,
- Luisa Ciminio,
- Iannis Aifantis,
- Chuan He,
- Francois Fuks,
- Martin S. Tallman,
- Adolfo Ferrando,
- Stephen Nimer,
- Elisabeth Paietta,
- Craig B. Thompson,
- Jonathan D. Licht,
- Christopher E. Mason,
- Lucy A. Godley,
- Ari Melnick,
- Maria E. Figueroa,
- Ross L. Levine
Affiliations
- Raajit Rampal
- 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
- Altuna Alkalin
- 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
- Jozef Madzo
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
- Aparna Vasanthakumar
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
- Elodie Pronier
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Jay Patel
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Yushan Li
- Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA
- Jihae Ahn
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Omar Abdel-Wahab
- 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
- Alan Shih
- 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
- Chao Lu
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Patrick S. Ward
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Jennifer J. Tsai
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA
- Todd Hricik
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Valeria Tosello
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA
- Jacob E. Tallman
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Xinyang Zhao
- Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Danette Daniels
- Promega Corporation, Madison, WI 53703, USA
- Qing Dai
- Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA
- Luisa Ciminio
- Department of Pathology, New York University Cancer Institute, New York, NY 10016, USA
- Iannis Aifantis
- Department of Pathology, New York University Cancer Institute, New York, NY 10016, USA
- Chuan He
- Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA
- Francois Fuks
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium
- Martin S. Tallman
- Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Adolfo Ferrando
- Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA
- Stephen Nimer
- Department of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
- Elisabeth Paietta
- Montefiore Medical Center, New York, NY 10466, USA
- Craig B. Thompson
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- Jonathan D. Licht
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA
- Christopher E. Mason
- 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; Corresponding author
- Lucy A. Godley
- 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; Corresponding author
- Ari Melnick
- Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Corresponding author
- Maria E. Figueroa
- Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author
- Ross L. Levine
- 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; Corresponding author
- Journal volume & issue
-
Vol. 9,
no. 5
pp. 1841 – 1855
Abstract
Summary: 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. : Mutational studies in patients with acute myeloid leukemia (AML) have identified recurrent mutations in TET2 and IDH1/IDH2, and these mutations result in a reduction in 5-hydroxymethylcytosine (5hmC) levels. Rampal et al. demonstrate that WT1 mutations anticorrelate with TET2 and IDH1/IDH2 mutations, and WT1 mutant AMLs have decreased 5hmC levels, consistent with reduced TET2 function.