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

ME Figueroa; O Abdel-Wahab; C Lu; PS Ward; J Patel; A Shih; YS Li; N Bhagwat; A Vasanthakumar; HF Fernandez; MS Tallman; ZX Sun; K Wolniak; Justine Peeters; W (Wei) Liu; SE Choe; VR Fantin; E Paietta; Bob Löwenberg; JD Licht; LA Godley; Ruud Delwel; Peter Valk; CB Thompson; RL Levine; A Melnick

doi:10.1016/j.ccr.2010.11.015

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

ME Figueroa, O Abdel-Wahab, C Lu, PS Ward, J Patel, A Shih, YS Li, N Bhagwat, A Vasanthakumar, HF Fernandez, MS Tallman, ZX Sun, K Wolniak, Justine Peeters, W (Wei) Liu, SE Choe, VR Fantin, E Paietta, Bob Löwenberg, JD LichtLA Godley, Ruud Delwel, Peter Valk, CB Thompson, RL Levine, A Melnick

Research output: Contribution to journal › Article › Academic › peer-review

2133 Citations (Scopus)

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 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.

Original language	Undefined/Unknown
Pages (from-to)	553-567
Number of pages	15
Journal	Cancer Cell
Volume	18
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2010.11.015
Publication status	Published - 2010

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10.1016/j.ccr.2010.11.015

http://hdl.handle.net/1765/21880

Cite this

Figueroa, ME., Abdel-Wahab, O., Lu, C., Ward, PS., Patel, J., Shih, A., Li, YS., Bhagwat, N., Vasanthakumar, A., Fernandez, HF., Tallman, MS., Sun, ZX., Wolniak, K., Peeters, J., Liu, W., Choe, SE., Fantin, VR., Paietta, E., Löwenberg, B., ... Melnick, A. (2010). Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation. Cancer Cell, 18(6), 553-567. https://doi.org/10.1016/j.ccr.2010.11.015

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

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 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.",

author = "ME Figueroa and O Abdel-Wahab and C Lu and PS Ward and J Patel and A Shih and YS Li and N Bhagwat and A Vasanthakumar and HF Fernandez and MS Tallman and ZX Sun and K Wolniak and Justine Peeters and Liu, {W (Wei)} and SE Choe and VR Fantin and E Paietta and Bob L{\"o}wenberg and JD Licht and LA Godley and Ruud Delwel and Peter Valk and CB Thompson and RL Levine and A Melnick",

year = "2010",

doi = "10.1016/j.ccr.2010.11.015",

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Figueroa, ME, Abdel-Wahab, O, Lu, C, Ward, PS, Patel, J, Shih, A, Li, YS, Bhagwat, N, Vasanthakumar, A, Fernandez, HF, Tallman, MS, Sun, ZX, Wolniak, K, Peeters, J, Liu, W, Choe, SE, Fantin, VR, Paietta, E, Löwenberg, B, Licht, JD, Godley, LA, Delwel, R , Valk, P, 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

TY - JOUR

T1 - Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

AU - Figueroa, ME

AU - Abdel-Wahab, O

AU - Lu, C

AU - Ward, PS

AU - Patel, J

AU - Shih, A

AU - Li, YS

AU - Bhagwat, N

AU - Vasanthakumar, A

AU - Fernandez, HF

AU - Tallman, MS

AU - Sun, ZX

AU - Wolniak, K

AU - Peeters, Justine

AU - Liu, W (Wei)

AU - Choe, SE

AU - Fantin, VR

AU - Paietta, E

AU - Löwenberg, Bob

AU - Licht, JD

AU - Godley, LA

AU - Delwel, Ruud

AU - Valk, Peter

AU - Thompson, CB

AU - Levine, RL

AU - Melnick, A

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1016/j.ccr.2010.11.015

DO - 10.1016/j.ccr.2010.11.015

M3 - Article

SN - 1535-6108

VL - 18

SP - 553

EP - 567

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -