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

Abstract

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-ketoglutarate1-6. 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 associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…The altered methylation patterns thereby promote dedifferentiation of the tumors. Consequently, the specific inhibition of the mutant isocitrate dehydrogenase enzyme normalizes the methylation pattern in the tumor and leads to differentiation of tumor cells and inhibition of tumor proliferation [207][208][209]. Mutant isocitrate dehydrogenase inhibitors thereby constitute an ideal case of a drug target, since the mutation is only present in the tumor but not in any healthy tissue throughout the body.…”

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

“…2HG accumulation competitively inhibits αKG-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family that regulate cellular epigenetic status (12)(13)(14)(15). This epigenetic dysregulation is associated with impairment of cellular differentiation in multiple cell types, including hematopoietic cells (15)(16)(17)(18)(19)(20)(21). AGI-6780, a selective sulfonamide inhibitor of the mutant IDH2 enzyme, lowered 2HG levels and induced differentiation of TF-1 erythroleukemia cells and primary human AML cells harboring the IDH2 R140Q mutation (17), providing in vitro evidence that inhibition of the mutant IDH2 enzyme can reverse some of the phenotypic changes it induces.…”

Molecular Genetics of Secondary Glioblastoma

“…Second, IDH mutation results in decreased production of α-KG, which impairs the function of many α-KG-dependent dioxygenases, including but not limited to histone demethylases (e.g., collagen prolyl-4-hydroxylase, prolyl hydroxylases, and the ten-eleven translocation (TET) family of DNA hydroxylases) (26). Change in histone methylation is thought to also interfere with the terminal differentiation of cells and may predispose cells harboring mutant IDH to malignant transformation (27). Based on the above evidence, IDH1/2 mutations have been termed as lineage markers by some authors (11), and it is now accepted as a more definitive marker of secondary GBM than any other clinical or pathological criterion (28).…”