2015
DOI: 10.18632/oncotarget.3723
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Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines

Abstract: Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found in a subset of benign and malignant cartilage tumors, gliomas and leukaemias. The mutant enzyme causes the production of D-2-hydroxyglutarate (D-2-HG), affecting CpG island and histone methylation. While mutations in IDH1/2 are early events in benign cartilage tumors, we evaluated whether these mutations play a role in malignant chondrosarcomas. Compared to IDH1/2 wildtype cell lines, chondrosarcoma cell lines harboring an endogenous IDH1 (n=3) … Show more

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Cited by 83 publications
(93 citation statements)
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“…Rohle et al reported removal of the repressive H3K9me3 and H3K27me3 marks after inhibition of mutant IDH1 using AGI-5198 in IDH1 mutant glioma cells [49]. In contrast to these findings in other tumour types, we showed previously that inhibition of mutant IDH1 in chondrosarcoma cell lines did not alter trimethylation of H3K4, H3K9 and H3K27 [50], which is in concordance with the present immunohistochemical results.…”
Section: Discussionsupporting
confidence: 92%
See 1 more Smart Citation
“…Rohle et al reported removal of the repressive H3K9me3 and H3K27me3 marks after inhibition of mutant IDH1 using AGI-5198 in IDH1 mutant glioma cells [49]. In contrast to these findings in other tumour types, we showed previously that inhibition of mutant IDH1 in chondrosarcoma cell lines did not alter trimethylation of H3K4, H3K9 and H3K27 [50], which is in concordance with the present immunohistochemical results.…”
Section: Discussionsupporting
confidence: 92%
“…We also showed that trimethylation of H3K4, H3K9 and H3K27 did not change using AGI-5198 [50]. On the other hand, we and others have shown that mutant IDH1 plays a crucial role in the early development of benign enchondromas, as osteoblast differentiation was inhibited while promoting chondrogenic differentiation of mesenchymal stem cells [62, 63].…”
Section: Discussionmentioning
confidence: 99%
“…Subsequent studies in a single mutant IDH1-containing patient-derived glioma xenograft suggested that exposures to the same IDH1-specific inhibitor suppressed 2-HG levels, reversed at least some of the mutant IDH1-driven epigenetic alterations, and also suppressed clonogenicity (16). Subsequent studies, however, using other mutant IDH1-containing cells reached more mixed results (26, 27), and the most recent studies with a series of xenografts derived primarily from patients with recurrent, mutant IDH-containing gliomas suggest that mutant IDH1 inhibitors have modest growth-suppressing effects (28). Although most of these studies used the same mutant IDH1 inhibitor (AGI-5198), all of the studies used cells in which mutant IDH1 was expressed in cells transformed by other means, or cells in which mutant IDH1 expression appeared to play a secondary role in the transformation process.…”
Section: Introductionmentioning
confidence: 99%
“…Little is known about the role of IDH1/2 mutations in late-stage cancer. It is plausible that with increasing mutational burden, the dependence of late-stage malignant tumours on IDH1/2 mutations decreases, diminishing the therapeutic index of IDH1/2-mutant inhibitors 37 38. On the other hand, metabolic stress that results from IDH1/2 mutations persists, and this metabolic vulnerability provides an excellent target for therapy irrespective of the tumour stage.…”
Section: Introductionmentioning
confidence: 99%