Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):12851-12856. doi: 10.1073/pnas.1817662116. Epub 2019 Jun 10.
Oncogenic IDH1/2 mutations produce 2-hydroxyglutarate (2HG), resulting in competitive inhibition of DNA and protein demethylation. IDH-mutant cancer cells show an inability to differentiate but whether 2HG accumulation is sufficient to perturb differentiation directed by lineage-specifying transcription factors is unknown. A MyoD-driven model was used to study the role of IDH mutations in the differentiation of mesenchymal cells. The presence of 2HG produced by oncogenic IDH2 blocks the ability of MyoD to drive differentiation into myotubes. DNA 5mC hypermethylation is dispensable while H3K9 hypermethylation is required for this differentiation block. IDH2-R172K mutation results in H3K9 hypermethylation and impaired accessibility at myogenic chromatin regions but does not result in genome-wide decrease in accessibility. The results demonstrate the ability of the oncometabolite 2HG to block transcription factor-mediated differentiation in a molecularly defined system.
致癌性 IDH1/2 突变会产生 2-羟基戊二酸（2HG），从而导致 DNA 和蛋白质去甲基化的竞争性抑制。IDH 突变型癌细胞表现出无法分化的特征，但 2HG 的积累是否足以扰乱由谱系特异性转录因子指导的分化尚不清楚。使用 MyoD 驱动的模型来研究 IDH 突变在间充质细胞分化中的作用。致癌性 IDH2 产生的 2HG 会阻止 MyoD 驱动分化为肌管的能力。DNA 5mC 高甲基化是可有可无的，而 H3K9 高甲基化对于这种分化阻断是必需的。IDH2-R172K 突变导致 H3K9 高甲基化和肌原性染色质区域的可及性受损，但不会导致全基因组可及性降低。这些结果表明，代谢物 2HG 能够在分子定义的系统中阻断转录因子介导的分化。
