Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2

Abstract

Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate, supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET-mediated DNA demethylation. Meta-analysis of the acute myeloid leukaemia, low-grade glioma, cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, we identify the transcription factor EBF1 (early B-cell factor 1) as an interaction partner for TET2, suggesting a sequence-specific mechanism for regulating DNA methylation.

CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice

“…Its tumor suppressive function might be linked to IDH1/IDH2, which carry oncogenic mutations in >10% of ICCs (23,24,41), leading to dioxigenase inhibition by 2-hydroxyglutarate production (42,43). Among the 70 2OG-dependent dioxigenases, TET2 is considered a promising cancer-relevant target: TET2 and IDH1/2 mutations induce similar hypermethylation phenotypes (41,44) and are mutually exclusive in AML, suggesting similar effects on cellular transformation (45). TET2 is not mutated in human ICC, but IDH1/2 alterations are associated with impaired TET2 function (41).…”

Aberrant DNA Methylations in Chondrosarcoma

“…2-hydroxyglutarate is an inhibitor of TET proteins that participate in DNA demethylation. Thus, increasing 2-hydroxyglutarate produced by mutant IDH results in genome-wide hypermethylation [31,32]. Collectively, IDH mutations can maintain appropriate DNA methylation of genes associated with regulation of cells differentiation and ultimately contribute to tumorigenesis [31,32].…”

“…Thus, increasing 2-hydroxyglutarate produced by mutant IDH results in genome-wide hypermethylation [31,32]. Collectively, IDH mutations can maintain appropriate DNA methylation of genes associated with regulation of cells differentiation and ultimately contribute to tumorigenesis [31,32]. In murine 10T1/2 mesenchymal progenitor cells, the expression of mutant IDH2 led to genome-wide DNA hypermethylation and impairment in the differentiation of mesenchymal cells, which could be reversed by treatment with azacytidine [31][32][33].…”

“…Collectively, IDH mutations can maintain appropriate DNA methylation of genes associated with regulation of cells differentiation and ultimately contribute to tumorigenesis [31,32]. In murine 10T1/2 mesenchymal progenitor cells, the expression of mutant IDH2 led to genome-wide DNA hypermethylation and impairment in the differentiation of mesenchymal cells, which could be reversed by treatment with azacytidine [31][32][33]. Therefore, further investigation into the genetic impact on DNA methylation in CS and the interaction between genetics and epigenetics is necessary for the understanding of initiation and progression of this malignancy.…”

“…IDH mutations (IDH1 and IDH2 mutations) are prevalent in more than 50% of patients with CS [31]. Mutant IDH in CS produces elevated 2-hydroxyglutarate compared with normal tissues [32].…”