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

被引：2119

作者：

Figueroa, Maria E. ^{[2
]}

Abdel-Wahab, Omar ^{[3
,4
]}

Lu, Chao ^{[1
]}

Ward, Patrick S. ^{[1
]}

Patel, Jay ^{[3
]}

Shih, Alan ^{[3
,4
]}

Li, Yushan ^{[2
]}

Bhagwat, Neha ^{[3
]}

Vasanthakumar, Aparna ^{[5
]}

Fernandez, Hugo F. ^{[6
]}

Tallman, Martin S. ^{[4
]}

Sun, Zhuoxin ^{[7
]}

Wolniak, Kristy ^{[8
]}

Peeters, Justine K. ^{[9
]}

Liu, Wei ^{[10
]}

Choe, Sung E. ^{[10
]}

Fantin, Valeria R. ^{[10
]}

Paietta, Elisabeth ^{[11
]}

Lowenberg, Bob ^{[9
]}

Licht, Jonathan D. ^{[8
]}

Godley, Lucy A. ^{[5
]}

Delwel, Ruud ^{[9
]}

Valk, Peter J. M. ^{[9
]}

Thompson, Craig B. ^{[1
]}

Levine, Ross L. ^{[3
,4
]}

Melnick, An ^{[2
]}

机构：

[1] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[2] Weill Cornell Med Coll, Div Hematol Oncol, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 USA

[5] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA

[6] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Bone Marrow Transplantat, Tampa, FL 33612 USA

[7] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02445 USA

[8] Northwestern Univ, Div Hematol Oncol, Chicago, IL 60611 USA

[9] Erasmus Univ, Med Ctr, Dept Hematol, NL-3000 CA Rotterdam, Netherlands

[10] Agios Pharmaceut, Cambridge, MA 02139 USA

[11] Montefiore Med Ctr, Ctr Canc, North Div, Bronx, NY 10466 USA

来源：

CANCER CELL | 2010年 / 18卷 / 06期

关键词：

ACUTE MYELOID-LEUKEMIA; ACQUIRED MUTATIONS; DNA; DEMETHYLATION; METHYLATION; CONVERSION; HELP;

D O I：

10.1016/j.ccr.2010.11.015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 alpha-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.

引用

页码：553 / 567

页数：15

共 29 条

[1] Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value [J].

Abbas, Saman ;

Lugthart, Sanne ;

Kavelaars, Francois G. ;

Schelen, Anita ;

Koenders, Jasper E. ;

Zeilemaker, Annelieke ;

van Putten, Wim J. L. ;

Rijneveld, Anita W. ;

Lowenberg, Bob ;

Valk, Peter J. M. .

BLOOD, 2010, 116 (12) :2122-2126

[2] Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies [J].

Abdel-Wahab, Omar ;

Mullally, Ann ;

Hedvat, Cyrus ;

Garcia-Manero, Guillermo ;

Patel, Jay ;

Wadleigh, Martha ;

Malinge, Sebastien ;

Yao, JinJuan ;

Kilpivaara, Outi ;

Bhat, Rukhmi ;

Huberman, Kety ;

Thomas, Sabrena ;

Dolgalev, Igor ;

Heguy, Adriana ;

Paietta, Elisabeth ;

Le Beau, Michelle M. ;

Beran, Miloslav ;

Tallman, Martin S. ;

Ebert, Benjamin L. ;

Kantarjian, Hagop M. ;

Stone, Richard M. ;

Gilliland, D. Gary ;

Crispino, John D. ;

Levine, Ross L. .

BLOOD, 2009, 114 (01) :144-147

[3] Cancer-associated IDH1 mutations produce 2-hydroxyglutarate [J].

Dang, Lenny ;

White, David W. ;

Gross, Stefan ;

Bennett, Bryson D. ;

Bittinger, Mark A. ;

Driggers, Edward M. ;

Fantin, Valeria R. ;

Jang, Hyun Gyung ;

Jin, Shengfang ;

Keenan, Marie C. ;

Marks, Kevin M. ;

Prins, Robert M. ;

Ward, Patrick S. ;

Yen, Katharine E. ;

Liau, Linda M. ;

Rabinowitz, Joshua D. ;

Cantley, Lewis C. ;

Thompson, Craig B. ;

Heiden, Matthew G. Vander ;

Su, Shinsan M. .

NATURE, 2009, 462 (7274) :739-U52

[4] Mutation in TET2 in Myeloid Cancers [J].

Delhommeau, Francois ;

Dupont, Sabrina ;

Della Valle, Veronique ;

James, Chloe ;

Trannoy, Severine ;

Masse, Aline ;

Kosmider, Olivier ;

Le Couedic, Jean-Pierre ;

Robert, Fabienne ;

Alberdi, Antonio ;

Lecluse, Yann ;

Plo, Isabelle ;

Dreyfus, Francois J. ;

Marzac, Christophe ;

Casadevall, Nicole ;

Lacombe, Catherine ;

Romana, Serge P. ;

Dessen, Philippe ;

Soulier, Jean ;

Viguie, Franck ;

Fontenay, Michaela ;

Vainchenker, William ;

Bernard, Olivier A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (22) :2289-2301

[5] Anthracycline Dose Intensification in Acute Myeloid Leukemia [J].

Fernandez, Hugo F. ;

Sun, Zhuoxin ;

Yao, Xiaopan ;

Litzow, Mark R. ;

Luger, Selina M. ;

Paietta, Elisabeth M. ;

Racevskis, Janis ;

Dewald, Gordon W. ;

Ketterling, Rhett P. ;

Bennett, John M. ;

Rowe, Jacob M. ;

Lazarus, Hillard M. ;

Tallman, Martin S. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (13) :1249-1259

[6] DNA Methylation Signatures Identify Biologically Distinct Subtypes in Acute Myeloid Leukemia [J].

Figueroa, Maria E. ;

Lugthart, Sanne ;

Li, Yushan ;

Erpelinck-Verschueren, Claudia ;

Deng, Xutao ;

Christos, Paul J. ;

Schifano, Elizabeth ;

Booth, James ;

van Putten, Wim ;

Skrabanek, Lucy ;

Campagne, Fabien ;

Mazumdar, Madhu ;

Greally, John M. ;

Valk, Peter J. M. ;

Lowenberg, Bob ;

Delwel, Ruud ;

Melnick, Ari .

CANCER CELL, 2010, 17 (01) :13-27

[7]

Figueroa Maria E., 2009, V538, P395, DOI 10.1007/978-1-59745-418-6_20

[8] Discovering Hematopoietic Mechanisms through Genome-wide Analysis of GATA Factor Chromatin Occupancy [J].

Fujiwara, Tohnu ;

O'Geen, Henriette ;

Keles, Sunduz ;

Blahnik, Kimberly ;

Linnemann, Amelia K. ;

Kang, Yoon-A. ;

Choi, Kyunghee ;

Farnham, Peggy J. ;

Bresnick, Emery H. .

MOLECULAR CELL, 2009, 36 (04) :667-681

[9] Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas [J].

Hartmann, Christian ;

Meyer, Jochen ;

Balss, Joerg ;

Capper, David ;

Mueller, Wolf ;

Christians, Arne ;

Felsberg, Joerg ;

Wolter, Marietta ;

Mawrin, Christian ;

Wick, Wolfgang ;

Weller, Michael ;

Herold-Mende, Christel ;

Unterberg, Andreas ;

Jeuken, Judith W. M. ;

Wesseling, Peter ;

Reifenberger, Guido ;

von Deimling, Andreas .

ACTA NEUROPATHOLOGICA, 2009, 118 (04) :469-474

[10] Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification [J].

Ito, Shinsuke ;

D'Alessio, Ana C. ;

Taranova, Olena V. ;

Hong, Kwonho ;

Sowers, Lawrence C. ;

Zhang, Yi .

NATURE, 2010, 466 (7310) :1129-U151

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