Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Cells

Badur, Mehmet G.; Muthusamy, Thangaselvam; Parker, Seth J.; Ma, Shenghong; McBrayer, Samuel K.; Cordes, Thekla; Magaña, Jose H.; Guan, Kun Liang; Metallo, Christian M.

doi:10.1016/j.celrep.2018.10.099

Cited by 26 publications

(23 citation statements)

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“…1 c). A negligible effect was observed in growth and viability (Additional Figure 1 C) of glioma cell lines upon treatment with 10 μM AGI5198 for 72 h in agreement with previous investigations involving models of chondrosarcoma [ 40 ] and fibrosarcoma [ 41 ], even a positive effect on proliferation has been recently reported in BT142 [ 42 ]. This observation may reveal that the inhibition of 2HG synthesis does not correlate to the regulation of cell growth and proliferation.…”

Section: Resultssupporting

confidence: 91%

Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition

et al. 2020

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Background Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1mut) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG). Methods We have employed a combination of 13C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1mut glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity. Results We report the adaptability of IDH1mut cells’ metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition. Conclusions Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1mut gliomas.

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Section: Resultssupporting

confidence: 91%

Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition

et al. 2020

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“…Importantly, and in addition to tumor cell-autonomous metabolic vulnerabilities conferred by IDH mutations [41][42][43] , our study reveals an unexpected function of R-2-HG in regulating amino acid metabolism in immune cells. R-2-HG is taken up by myeloid cells to enzymatically induce TDO2-dependent activation of the kynurenine pathway and, subsequently, the AHR.…”

Section: Discussionmentioning

confidence: 77%

Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas

et al. 2021

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The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.

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“…Recent studies have indicated that the metabolome altered by mutant IDH1/2 can be targeted for cancer therapy. 42,43 Thus, targeting altered metabolome can be another strategy for of IDH1/2-mutant leukemia as an alternative to the inhibition of mutant IDH; this has also been suggested by another pioneering unpublished study. 44 Considering the newly discovered IDH2-inhibitor-resistant secondary IDH2 mutation, 45,46 the search for new therapeutic targets under mutant IDH2 background is important.…”

Section: Discussionmentioning

confidence: 91%

Dnmt3a loss and Idh2 neomorphic mutations mutually potentiate malignant hematopoiesis

Zhang

Wang

et al. 2020

Blood

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Mutations in the epigenetic regulators DNMT3A and IDH1/2 co-occur in patients with acute myeloid leukemia and lymphoma. In this study, these 2 epigenetic mutations cooperated to induce leukemia. Leukemia-initiating cells from Dnmt3a−/− mice that express an IDH2 neomorphic mutant have a megakaryocyte-erythroid progenitor–like immunophenotype, activate a stem-cell–like gene signature, and repress differentiated progenitor genes. We observed an epigenomic dysregulation with the gain of repressive H3K9 trimethylation and loss of H3K9 acetylation in diseased mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). HDAC inhibitors rapidly reversed the H3K9 methylation/acetylation imbalance in diseased mouse HSPCs while reducing the leukemia burden. In addition, using targeted metabolomic profiling for the first time in mouse leukemia models, we also showed that prostaglandin E2 is overproduced in double-mutant HSPCs, rendering them sensitive to prostaglandin synthesis inhibition. These data revealed that Dnmt3a and Idh2 mutations are synergistic events in leukemogenesis and that HSPCs carrying both mutations are sensitive to induced differentiation by the inhibition of both prostaglandin synthesis and HDAC, which may reveal new therapeutic opportunities for patients carrying IDH1/2 mutations.

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Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Cells

Cited by 26 publications

References 0 publications

Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition

Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition

Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas

Dnmt3a loss and Idh2 neomorphic mutations mutually potentiate malignant hematopoiesis

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