IDH Mutation, Competitive Inhibition of FTO, and RNA Methylation

Elkashef, Sara M.; An, Lin; Myers, Jamie; Sill, Heinz; Jiang, Daifeng; Dahia, Patricia L.M.; Aguiar, Ricardo C.T.

doi:10.1016/j.ccell.2017.04.001

Cited by 69 publications

(54 citation statements)

References 5 publications

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“…RNA demethylases are α-ketoglutarate-dependent dioxygenases that can be inhibited by DMOG 19 . Such inhibition would be expected to increase the steady-state levels of m6A.…”

Section: Resultsmentioning

confidence: 99%

Discovery of RNA-binding proteins and characterization of their dynamic responses by enhanced RNA interactome capture

et al. 2018

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Following the realization that eukaryotic RNA-binding proteomes are substantially larger than anticipated, we must now understand their detailed composition and dynamics. Methods such as RNA interactome capture (RIC) have begun to address this need. However, limitations of RIC have been reported. Here we describe enhanced RNA interactome capture (eRIC), a method based on the use of an LNA-modified capture probe, which yields numerous advantages including greater specificity and increased signal-to-noise ratios compared to existing methods. In Jurkat cells, eRIC reduces the rRNA and DNA contamination by >10-fold compared to RIC and increases the detection of RNA-binding proteins. Due to its low background, eRIC also empowers comparative analyses of changes of RNA-bound proteomes missed by RIC. For example, in cells treated with dimethyloxalylglycine, which inhibits RNA demethylases, eRIC identifies m6A-responsive RNA-binding proteins that escape RIC. eRIC will facilitate the unbiased characterization of RBP dynamics in response to biological and pharmacological cues.

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“…RNA demethylases are α-ketoglutarate-dependent dioxygenases that can be inhibited by DMOG 19 . Such inhibition would be expected to increase the steady-state levels of m6A.…”

Section: Resultsmentioning

confidence: 99%

Discovery of RNA-binding proteins and characterization of their dynamic responses by enhanced RNA interactome capture

et al. 2018

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“…In addition to TET enzymes, D2HG can inhibit the N6-methyladenosine (m6A) RNA demethylase fat mass and obesity associated protein (FTO), another α-KG-dependent dioxygenase 15 . This leads to significantly higher m6A levels in IDH1/2-mutant than in IDH1/2-wild-type AML, despite comparable FTO expression 90 . Although evidence points to an oncogenic role of FTO in AML 15 , a recent study suggested that inhibition of FTO by accumulated D2HG may have opposing pro-and anti-tumour effects in both AML and glioma, dependent on the mutation status of IDH, and the abundance of FTO and MYC 98 .…”

Section: [H2] Methylation Deregulation In Cancermentioning

confidence: 97%

“…These mechanisms include mutations in metabolic enzymes, resulting in production of oncometabolites [G] that essentially poison the iron-dependent dioxygenases that regulate histone and DNA demethylation, and somatic mutations in the core histone genes that lead to a global loss of the histone modifications ( Figure 3). D-2-hydroxyglutarate (D2HG) is one such oncometabolite, which inhibits numerous demethylases, leading to changes in genomic and transcriptomic methylation profiles as well as gene expression and genome topology 32,[90][91][92] . Oncogenesis has been associated with specific mutations in isocitrate dehydrogenases (IDHs), which prevent conversion of isocitrate to αketoglutarate (α-KG) and additionally promote the reduction of α-KG to the structural analog D2HG 93,94 .…”

Section: [H2] Methylation Deregulation In Cancermentioning

confidence: 99%

The roles of DNA, RNA and histone methylation in ageing and cancer

Michalak

Burr

Bannister

et al. 2019

Nat Rev Mol Cell Biol

396

321

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Chromatin is a macromolecular complex predominantly comprising DNA, histones and RNA. Its methylation is highly conserved throughout phylogeny as it provides an instructive template that helps coordinate context dependent access for gene expression, DNA repair and DNA replication. Dynamic changes in chromatin methylation are central to cell fate determination and normal development of the organism. Consequently, inherited or acquired mutations in the major epigenetic protagonists that regulate methylation of DNA, RNA and/or histone proteins are commonly observed in developmental disorders, ageing and cancer. This has provided the impetus for the clinical development of epigenetic therapies aimed to reset the methylation imbalance observed in these conditions. In this review we discuss the key principles of chromatin methylation and focus on how this fundamental biological process is corrupted in cancer. We discuss methylation-based cancer therapies and provide a perspective on the emerging data from early phase clinical trials therapies that target regulators of DNA and histone methylation. We also highlight promising future strategies, including monitoring chromatin methylation for diagnostic purposes and combination epigenetic therapy strategies that may improve immune surveillance in cancer and increase the efficacy of conventional and targeted anti-cancer drugs.

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“…As an α-ketoglutarate (α-KG)-dependent dioxygenase, FTO enzymatic activity can be competitively inhibited by the structurally related metabolite D-2-hydroxyglutarate (D-2HG), which aberrantly accumulates in isocitrate dehydrogenase 1 or 2 (IDH1/2)-mutant AMLs. It has been shown that in a number of IDH1/2-mutant AML patient samples, the global m 6 A is increased due to inhibition of FTO activity without any change in FTO expression (78). Thereby, in certain cases of AML, in particular AML with mutant IDH1/2, inhibition of FTO function appears to be favorable for leukemia cells.…”

Section: The Role Of M 6 a In Malignant Hematopoiesismentioning

confidence: 99%

The Biology of m6A RNA Methylation in Normal and Malignant Hematopoiesis

2019

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Hematopoietic development and differentiation are highly regulated processes, and recent studies focusing on m 6 A mRNA methylation have uncovered how this mark controls cell fate in both normal and malignant hematopoietic states. In this review, we focus on how writers, readers, and erasers of RNA methylation can mediate distinct phenotypes on mRNAs and on cells. Targeting the RNA methylation program has emerged as a potential novel therapeutic strategy, and we explore the role for these regulators in both normal and dysregulated cell contexts. Signifi cance: RNA methylation is required for cancer cell survival in solid tumors and in acute myeloid leukemia, and targeting this pathway has been proposed as a new therapeutic strategy in cancer. However, understanding the role for RNA methylation in both normal and malignant states is essential for understanding the potential consequences for therapeutic intervention.

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IDH Mutation, Competitive Inhibition of FTO, and RNA Methylation

Cited by 69 publications

References 5 publications

Discovery of RNA-binding proteins and characterization of their dynamic responses by enhanced RNA interactome capture

Discovery of RNA-binding proteins and characterization of their dynamic responses by enhanced RNA interactome capture

The roles of DNA, RNA and histone methylation in ageing and cancer

The Biology of m6A RNA Methylation in Normal and Malignant Hematopoiesis

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