Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation
Cancer Cell, Volume 18, Issue 6, 553-567, 02 December 2010
Copyright © 2010 Elsevier Inc. All rights reserved.
Maria E. Figueroa, Omar Abdel-Wahab, Chao Lu, Patrick S. Ward, Jay Patel, Alan Shih, Yushan Li, Neha Bhagwat, Aparna Vasanthakumar, Hugo F. Fernandez, Martin S. Tallman, Zhuoxin Sun, Kristy Wolniak, Justine K. Peeters, Wei Liu, Sung E. Choe, Valeria R. Fantin, Elisabeth Paietta, Bob Löwenberg, Jonathan D. Licht, Lucy A. Godley, Ruud Delwel, Peter J.M. Valk, Craig B. Thompsonsend email, Ross L. Levinesend email, Ari Melnick
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Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA Department of Blood and Bone Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA Dana Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02445, USA Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands Agios Pharmaceuticals, Cambridge, MA 02139, USA Cancer Center, Montefiore Medical Center–North Division, Bronx, NY 10466, USA Corresponding author These authors contributed equally to this work
* IDH1/2 mutations associate with a specific DNA hypermethylation profile
* Expression of mutant IDH1/2 induces an increase in global 5-methylcytosine levels
* IDH1/2 mutations inhibit the hydroxylation reaction of methylcytosine by TET2
* Expression of IDH2 mutants as well as loss of TET2 impair myeloid differentiation
Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2-hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations were associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect.
Cancer Cell - Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation
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