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 M. Paietta, Bob Löwenberg, Jonathan D. LichtLucy A. Godley, Ruud Delwel, Peter J M Valk, Craig B. Thompson, Ross L. Levine, Ari Melnick

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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.

Original languageEnglish (US)
Pages (from-to)553-567
Number of pages15
JournalCancer Cell
Volume18
Issue number6
DOIs
StatePublished - Dec 14 2010

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Epigenomics
Phenotype
Mutation
Acute Myeloid Leukemia
Stem Cells
DNA
Enzymes
Alleles
Neoplasms
alpha-hydroxyglutarate

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation. / Figueroa, Maria E.; Abdel-Wahab, Omar; Lu, Chao; Ward, Patrick S.; Patel, Jay; Shih, Alan; Li, Yushan; Bhagwat, Neha; Vasanthakumar, Aparna; Fernandez, Hugo F.; Tallman, Martin S.; Sun, Zhuoxin; Wolniak, Kristy; Peeters, Justine K.; Liu, Wei; Choe, Sung E.; Fantin, Valeria R.; Paietta, Elisabeth M.; Löwenberg, Bob; Licht, Jonathan D.; Godley, Lucy A.; Delwel, Ruud; Valk, Peter J M; Thompson, Craig B.; Levine, Ross L.; Melnick, Ari.

In: Cancer Cell, Vol. 18, No. 6, 14.12.2010, p. 553-567.

Research output: Contribution to journalArticle

Figueroa, ME, Abdel-Wahab, O, Lu, C, Ward, PS, Patel, J, Shih, A, Li, Y, Bhagwat, N, Vasanthakumar, A, Fernandez, HF, Tallman, MS, Sun, Z, Wolniak, K, Peeters, JK, Liu, W, Choe, SE, Fantin, VR, Paietta, EM, Löwenberg, B, Licht, JD, Godley, LA, Delwel, R, Valk, PJM, Thompson, CB, Levine, RL & Melnick, A 2010, 'Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation', Cancer Cell, vol. 18, no. 6, pp. 553-567. https://doi.org/10.1016/j.ccr.2010.11.015
Figueroa, Maria E. ; Abdel-Wahab, Omar ; Lu, Chao ; Ward, Patrick S. ; Patel, Jay ; Shih, Alan ; Li, Yushan ; Bhagwat, Neha ; Vasanthakumar, Aparna ; Fernandez, Hugo F. ; Tallman, Martin S. ; Sun, Zhuoxin ; Wolniak, Kristy ; Peeters, Justine K. ; Liu, Wei ; Choe, Sung E. ; Fantin, Valeria R. ; Paietta, Elisabeth M. ; Löwenberg, Bob ; Licht, Jonathan D. ; Godley, Lucy A. ; Delwel, Ruud ; Valk, Peter J M ; Thompson, Craig B. ; Levine, Ross L. ; Melnick, Ari. / Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation. In: Cancer Cell. 2010 ; Vol. 18, No. 6. pp. 553-567.
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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.",
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AU - Ward, Patrick S.

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AU - Shih, Alan

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AU - Paietta, Elisabeth M.

AU - Löwenberg, Bob

AU - Licht, Jonathan D.

AU - Godley, Lucy A.

AU - Delwel, Ruud

AU - Valk, Peter J M

AU - Thompson, Craig B.

AU - Levine, Ross L.

AU - Melnick, Ari

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