2-Hydroxyglutarate destabilizes chromatin regulatory landscape and lineage fidelity to promote cellular heterogeneity

Kusi, Meena; Zand, Maryam; Lin, Long-Yau; Chen, Meizhen; Lopez, Anthony; Lin, Chun-Lin; Wang, Chiou‐Miin; Lucio, Nicholas D.; Kirma, Nameer B.; Ruan, Jianhua; Huang, Tim H.M.; Mitsuya, Kohzoh

doi:10.1016/j.celrep.2021.110220

Cited by 13 publications

(4 citation statements)

References 92 publications

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“…Other cluster 8 and 10 metabolites are predicted to be synthesized by the nematode but not the bacterium. These include the sphingolipid metabolite phosphorylethanolamine ( 45 ) and 2-hydroxyglutaric acid, a butanoate pathway-derived metabolite that, in mammalian cells, serves as an oncometabolite that influences DNA repair and chromatin structure ( 46 ). Among the cluster 8 and 10 metabolites predicted to be specific to bacterial physiology is the polyamine acetyl-putrescine (cluster 8).…”

Section: Resultsmentioning

confidence: 99%

Apex Predator Nematodes and Meso-Predator Bacteria Consume Their Basal Insect Prey through Discrete Stages of Chemical Transformations

et al. 2022

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The processes by which organic life is consumed and reborn in a complex ecosystem were investigated through a multiomics approach applied to the tripartite Xenorhabdus bacterium- Steinernema nematode- Galleria insect symbiosis. Trophic analyses demonstrate the primary consumers of the insect are the bacteria, and the nematode in turn consumes the bacteria.

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Section: Resultsmentioning

confidence: 99%

Apex Predator Nematodes and Meso-Predator Bacteria Consume Their Basal Insect Prey through Discrete Stages of Chemical Transformations

et al. 2022

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“…Specifically, under conditions that typically promote erythroid differentiation, the expression of IDH2R140Q in TF-1 cells increased DNA methylation and H3K9me3 at the promoter of a key differentiation gene, HBG , suppressed HBG expression and blocked differentiation, all of which were reversed upon inhibition of mutant-IDH [ 40 ]. Aberrant DNA and histone methylation have also been reported in mutant-IDH expressing haematopoietic stem and progenitor cells in vivo [ 23 , 39 ] and in numerous studies where 2-HG is supplemented or mutant-IDH expressed in non-haematological malignancies [ 22 , 31 , 35 , 45 , 47–51 ]. Moreover, analyses of AML patient samples have shown that DNA hypermethylation in TET2-mutant AMLs overlaps with the hypermethylation phenotype of IDH-mutant AML [ 44 , 52 , 53 ].…”

Section: Biology Of Idh Mutations In Amlmentioning

confidence: 99%

The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

Gruber

Kats

2023

Biochemical Society Transactions

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Of the many genetic alterations that occur in cancer, relatively few have proven to be suitable for the development of targeted therapies. Mutations in isocitrate dehydrogenase (IDH) 1 and -2 increase the capacity of cancer cells to produce a normally scarce metabolite, D-2-hydroxyglutarate (2-HG), by several orders of magnitude. The discovery of the unusual biochemistry of IDH mutations spurred a flurry of activity that revealed 2-HG as an ‘oncometabolite’ with pleiotropic effects in malignant cells and consequences for anti-tumour immunity. Over the next decade, we learned that 2-HG dysregulates a wide array of molecular pathways, among them a large family of dioxygenases that utilise the closely related metabolite α-ketoglutarate (α-KG) as an essential co-substrate. 2-HG not only contributes to malignant transformation, but some cancer cells become addicted to it and sensitive to inhibitors that block its synthesis. Moreover, high 2-HG levels and loss of wild-type IDH1 or IDH2 activity gives rise to synthetic lethal vulnerabilities. Herein, we review the biology of IDH mutations with a particular focus on acute myeloid leukaemia (AML), an aggressive disease where selective targeting of IDH-mutant cells is showing significant promise.

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“…Beyond the impact of those changes on the cell's metabolism, epigenome regulators are also highly sensitive to changes in intracellular metabolism. Indeed, a cancer cell's epigenetic and transcriptional landscape can be altered, for example, by iron endocytosis (54), proline metabolism (55), or the metabolite 2-hydroxyglutarate (56).…”

Section: Cellular Plasticity As a Driver Of Cancer Progressionmentioning

confidence: 99%

Mapping Phenotypic Plasticity upon the Cancer Cell State Landscape Using Manifold Learning

et al. 2022

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Phenotypic plasticity describes the ability of cancer cells to undergo dynamic, nongenetic cell state changes that amplify cancer heterogeneity to promote metastasis and therapy evasion. Thus, cancer cells occupy a continuous spectrum of phenotypic states connected by trajectories defining dynamic transitions upon a cancer cell state landscape. With technologies proliferating to systematically record molecular mechanisms at single-cell resolution, we illuminate manifold learning techniques as emerging computational tools to effectively model cell state dynamics in a way that mimics our understanding of the cell state landscape. We anticipate that “state-gating” therapies targeting phenotypic plasticity will limit cancer heterogeneity, metastasis, and therapy resistance. Significance: Nongenetic mechanisms underlying phenotypic plasticity have emerged as significant drivers of tumor heterogeneity, metastasis, and therapy resistance. Herein, we discuss new experimental and computational techniques to define phenotypic plasticity as a scaffold to guide accelerated progress in uncovering new vulnerabilities for therapeutic exploitation.

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2-Hydroxyglutarate destabilizes chromatin regulatory landscape and lineage fidelity to promote cellular heterogeneity

Cited by 13 publications

References 92 publications

Apex Predator Nematodes and Meso-Predator Bacteria Consume Their Basal Insect Prey through Discrete Stages of Chemical Transformations

Apex Predator Nematodes and Meso-Predator Bacteria Consume Their Basal Insect Prey through Discrete Stages of Chemical Transformations

The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

Mapping Phenotypic Plasticity upon the Cancer Cell State Landscape Using Manifold Learning

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