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 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/progenitor cell marker expression, suggesting a shared proleukemogenic effect.

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

“…In support of this idea, studies have predominantly demonstrated hypermethylation signatures in both TET2-and IDH-mutant acute myeloid leukemias, 28 as well as in IDHmutant gliomas 29 and enchondromas, 32 although other authors have reported conflicting results. 41 However, although inhibition of TET function appears to be associated with DNA hypermethylation, it remains unclear how these epigenetic changes regulate gene expression, as studies have, as of yet, failed to demonstrate direct links between changes in the promoter methylation status of specific genes and alterations in the expression levels of those genes.…”

“…27 TET proteins are thought to have a role in tumor development, as inhibition of TET activity, as well as alteration of global DNA methylation, has been demonstrated in multiple tumor types. [28][29][30][31][32] Thus, succinate accumulation in the context of SDH deficiency could potentially drive tumorigenesis via the inhibition of TET family proteins and subsequent changes in DNA methylation and gene expression patterns. Indeed, recent work has shown that siRNA-mediated knockdown of SDHA in cultured cells and in mice leads to an inhibition of TET activity and decreased levels of 5-hmC.…”

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

“…D-2HG inhibits a large family of >70 different αKG-dependent enzymes that regulate chromatin-modifications, stability of hypoxia-inducible factors, extracellular matrix maturation, and DNA repair 1 . In particular, D-2HG-mediated inhibition of chromatin-modifying enzymes impairs induction of gene expression programs required for normal cell differentiation and ‘locks’ malignant cells in an undifferentiated stem cell-like state 5–7 . The relative contributions of different D-2HG targets to oncogenesis likely varies depending on the cellular context 8,9 .…”

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

“…Much like SDH‐ and FH‐mutated tumors, IDH‐mutated cells and tumors have been shown to exhibit a hypermethylator phenotype through the inhibition of the ten‐eleven translocation (TET) family of DNA demethylases and members of the Jumonji C‐domain histone demethylases through the competitive inhibition of αKG binding by (R)‐2HG 105, 106, 107, 108, 109. However, unlike SDH and FH mutations, the effect of (R)‐2HG on PHD activity has been the subject of some controversy.…”