Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

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 Thompson; Ross L Levine; Ari Melnick

doi:10.1016/j.ccr.2010.11.015

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Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

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Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

Maria E Figueroa, Omar Abdel-Wahab, Chao Lu, Patrick S Ward, Jay Patel, Alan Shih, Yushan Li, Neha Bhagwat, Aparna Vasanthakumar, Hugo F Fernandez, …

Cancer cell, Vol.18(6), pp.553-567

2010

DOI: https://doi.org/10.1016/j.ccr.2010.11.015

PMCID: PMC4105845

PMID: 21130701

Abstract

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. ► 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

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.103 Blood Disorders; 1.103.155 Acute Myeloid Leukemia
Web Of Science research areas: Cell Biology; Oncology
ESI research areas: Molecular Biology & Genetics

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Title: Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation
Creators: Maria E Figueroa - Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA
Omar Abdel-Wahab - Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Chao Lu - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
Patrick S Ward - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
Jay Patel - Human Oncology and Pathogenesis Program, 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
Yushan Li - Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA
Neha Bhagwat - Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Aparna Vasanthakumar - Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
Hugo F Fernandez - Department of Blood and Bone Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA
Martin S Tallman - Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Zhuoxin Sun - Dana Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02445, USA
Kristy Wolniak - Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA
Justine K Peeters - Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands
Wei Liu - Agios Pharmaceuticals, Cambridge, MA 02139, USA
Sung E Choe - Agios Pharmaceuticals, Cambridge, MA 02139, USA
Valeria R Fantin - Agios Pharmaceuticals, Cambridge, MA 02139, USA
Elisabeth Paietta - Cancer Center, Montefiore Medical Center–North Division, Bronx, NY 10466, USA
Bob Löwenberg - Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands
Jonathan D Licht - Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA
Lucy A Godley - Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
Ruud Delwel - Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands
Peter J.M Valk - Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands
Craig B Thompson - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
Ross L Levine - Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
Ari Melnick - Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10065, USA
Publication Details: Cancer cell, Vol.18(6), pp.553-567
Publisher: Elsevier Inc
Academic Unit: Miller School of Medicine; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 21130701
PMCID: PMC4105845
Record Identifier: 991031599026802976