Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic 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.
Weill Cornell Medical College, New York, NY 10065, USA.
Maria E
ME
Figueroa
Omar
O
Abdel-Wahab
Chao
C
Lu
Patrick S
PS
Ward
Jay
J
Patel
Alan
A
Shih
Yushan
Y
Li
Neha
N
Bhagwat
Aparna
A
Vasanthakumar
Hugo F
HF
Fernandez
Martin S
MS
Tallman
Zhuoxin
Z
Sun
Kristy
K
Wolniak
Justine K
JK
Peeters
Wei
W
Liu
Sung E
SE
Choe
Valeria R
VR
Fantin
Elisabeth
E
Paietta
Bob
B
Löwenberg
Jonathan D
JD
Licht
Lucy A
LA
Godley
Ruud
R
Delwel
Peter J M
PJ
Valk
Craig B
CB
Thompson
Ross L
RL
Levine
Ari
A
Melnick
D044503:5-Methylcytosine / Q000378:metabolism; D002454:Cell Differentiation; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049308:Dioxygenases; D050982:GATA1 Transcription Factor / Q000378:metabolism; D053263:Gene Regulatory Networks; D006801:Humans; D006900:Hydroxylation; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D000074008:MDS1 and EVI1 Complex Locus Protein; D009154:Mutation; D022423:Myeloid Cells / Q000166:cytology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D011519:Proto-Oncogenes; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D044503:5-Methylcytosine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human