Unknown,Transcriptomics,Genomics,Proteomics

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Patient glioma microarray for Impaired histone demethylation contributes to the cell differentiation arrest induced by cancer-associated isocitrate dehydrogenase mutation

ABSTRACT: To study the effects of IDH mutations, we collected and performed gene expression microarray analysis with tumor specimens from patients with grade II-III oligodendroglioma. Sequencing for mutations of IDH1 and IDH2 was done. Gene expression was compared between IDH wildtype vs. mutant samples

ORGANISM(S): Homo sapiens

SUBMITTER: Chao Lu

PROVIDER: E-MEXP-3239 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

IDH mutation impairs histone demethylation and results in a block to cell differentiation.

Lu Chao C Ward Patrick S PS Kapoor Gurpreet S GS Rohle Dan D Turcan Sevin S Abdel-Wahab Omar O Edwards Christopher R CR Khanin Raya R Figueroa Maria E ME Melnick Ari A Wellen Kathryn E KE O'Rourke Donald M DM Berger Shelley L SL Chan Timothy A TA Levine Ross L RL Mellinghoff Ingo K IK Thompson Craig B CB

Nature 20120215 7390

Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were ...[more]

PMID: 22343901

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Project description:Gene expression of mouse hepatoblasts (HBs) expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays that were processed at the Dana-Farber Cancer Institute core facility (http://macf-web.dfci.harvard.edu/) using their standard protocol. Mutations in Isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly primary liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alphaketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks primary liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF4a, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models (GEMMs) expressing mutant IDH in the adult liver show aberrant response to hepatic injury, characterized by HNF4a silencing, impaired hepatocyte differentiation and markedly elevated levels of cell proliferation. Moreover, mutant IDH and activated Kras, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis and present a novel GEMM of IDH-driven malignancy. Gene expression of HBs expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls under a doxycycline-inducible system (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays.

Dataset Information

Patient glioma microarray for Impaired histone demethylation contributes to the cell differentiation arrest induced by cancer-associated isocitrate dehydrogenase mutation

Publications

IDH mutation impairs histone demethylation and results in a block to cell differentiation.

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