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

被引：128

作者：

Guilhamon, Paul ^{[1
]}

Eskandarpour, Malihe ^{[1
]}

Halai, Dina ^{[2
]}

Wilson, Gareth A. ^{[1
]}

Feber, Andrew ^{[1
]}

Teschendorff, Andrew E. ^{[1
]}

Gomez, Valenti ^{[3
]}

Hergovich, Alexander ^{[3
]}

Tirabosco, Roberto ^{[2
]}

Amary, M. Fernanda ^{[2
]}

Baumhoer, Daniel ^{[4
]}

Jundt, Gernot ^{[4
]}

Ross, Mark T. ^{[5
]}

Flanagan, Adrienne M. ^{[1
,2
]}

Beck, Stephan ^{[1
]}

机构：

[1] UCL, UCL Canc Inst, London, England

[2] Royal Natl Orthopaed Hosp NHS Trust, Dept Histopathol, Stanmore, Middx, England

[3] UCL, UCL Canc Inst, Tumour Suppressor Signalling Networks, London, England

[4] Univ Basel Hosp, Inst Pathol, Bone Tumor Reference Ctr, CH-4031 Basel, Switzerland

[5] Illumina Cambridge Ltd, Saffron Walden, England

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

基金：

欧盟第七框架计划; 英国惠康基金; 英国医学研究理事会;

关键词：

RETINOIC ACID RECEPTORS; METHYLATION; MUTATIONS; DNA; 5-METHYLCYTOSINE; MECHANISMS; GLIOMA;

D O I：

10.1038/ncomms3166

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：9

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