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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 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 rapidly 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 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 cell marker expression, suggesting a shared pro-leukemogenic effect. Overall design: DNA methylation and gene expression profiling in IDH1/2 mutant vs. IDH1/2 wild-type AML

INSTRUMENT(S): HG17_Human_60mer_1in2

ORGANISM(S): Homo sapiens  

SUBMITTER: Maria Eugenia Figueroa   

PROVIDER: GSE24505 | GEO |

SECONDARY ACCESSION(S): PRJNA132611

REPOSITORIES: GEO

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