IDH mutations in glioma and acute myeloid leukemia

Dang, Lenny; Jin, Shengfang; Su, Shinsan M.

doi:10.1016/j.molmed.2010.07.002

Cited by 324 publications

(281 citation statements)

References 81 publications

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“…G6PD deficiency increases oxidative stress in red blood cells, causing hemolysis, which destructs red blood cells and releases hemoglobin to plasma. G6PD deficiency has not been found to be protective against cancers, possibly because of the compensatory effects from other NADPH-producing enzymes (20,34,35). Although large-scale epidemiological studies on the protective roles of G6PD deficiency against cancers are awaited, the pathophysiology of G6PD deficiency suggested that systemic suppression of NADPH production may adversely cause side effects similar to the symptoms of G6PD deficiency.…”

Section: Discussionmentioning

confidence: 99%

Transketolase counteracts oxidative stress to drive cancer development

Lai

Lin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

191

208

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Cancer cells experience an increase in oxidative stress. The pentose phosphate pathway (PPP) is a major biochemical pathway that generates antioxidant NADPH. Here, we show that transketolase (TKT), an enzyme in the PPP, is required for cancer growth because of its ability to affect the production of NAPDH to counteract oxidative stress. We show that TKT expression is tightly regulated by the Nuclear Factor, Erythroid 2-Like 2 (NRF2)/Kelch-Like ECHAssociated Protein 1 (KEAP1)/BTB and CNC Homolog 1 (BACH1) oxidative stress sensor pathway in cancers. Disturbing the redox homeostasis of cancer cells by genetic knockdown or pharmacologic inhibition of TKT sensitizes cancer cells to existing targeted therapy (Sorafenib). Our study strengthens the notion that antioxidants are beneficial to cancer growth and highlights the therapeutic benefits of targeting pathways that generate antioxidants.M etabolic reprogramming has recently been recognized as a hallmark of cancer (1). Cancer cells preferentially use glycolysis instead of oxidative phosphorylation to generate energy even in the presence of oxygen (O 2 ). This metabolic shift, named the Warburg Effect, channels glucose intermediates for macromolecule and antioxidant synthesis. A very important metabolic pathway that connects with glycolysis is the pentose phosphate pathway (PPP). The major goal of the PPP is the production of ribose-5-phosphate (R5P) and NADPH. R5P is the major backbone of RNA and is critical to nucleotide synthesis. NADPH is the major antioxidant that maintains the two major redox molecules, glutathione and thioredoxin, in the reduced state. NADPH therefore counteracts reactive oxygen species (ROS), enabling cancer cells to survive oxidative stress.The PPP is composed of the oxidative and nonoxidative arms. The oxidative arm of the PPP produces NADPH and ribose by three irreversible steps. First, glucose-6-phosphate dehydrogenase (G6PD) converts glucose-6-phosphate (G6P) to 6-phospho-gluconolactone and NAPDH. Second, phosphogluconolactonase converts 6-phospho-gluconolactone to 6-phosphogluconate. Third, 6-phosphogluconate dehydrogenase converts 6-phosphogluconate to ribulose-5-phosphate (Ru5P) and NAPDH. Ru5P then enters the nonoxidative arm of the PPP. Ru5P is converted to xylulose-5-phosphate (X5P) and Ru5P by epimerase and isomerase, respectively. The transketolase (TKT) family [transketolase-like 1 (TKTL1) and TKTL2] transfers two-carbon groups from X5P to R5P to generate sedoheptulose-7-phosphate (S7P) to glyceraldehyde-3-phosphate (G3P). Transaldolase (TALDO) transfers three-carbon groups from S7P to G3P to generate erythrose-4-phosphate (E4P) and fructose-6-phosphate (F6P). Finally, TKT transfers two-carbon groups from X5P to E4P to generate G3P and F6P, which reenter glycolysis. All enzymes in the nonoxidative arm of the PPP are reversible, allowing cells to adapt to the dynamic metabolic demands. When cells experience high oxidative stress, metabolites from the nonoxidative arm are rechanneled into glycolysis to refill the oxidative arm for...

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Section: Discussionmentioning

confidence: 99%

Transketolase counteracts oxidative stress to drive cancer development

Lai

Lin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

191

208

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“…The presence of mutant isocitrate dehydrogenase in the cell leads to the production of 2-hydroxyglutarate from α-ketoglutarate, which is the product of the non-mutated isocitrate dehydrogenase reaction. Since 2-hydroxyglutarate is an endpoint metabolite that is not further converted, it rapidly accumulates in the cells and outcompetes the structurally similar α-ketoglutarate as a cofactor for α-ketoglutarate-dependent dioxygenases [204,205]. This leads to an inhibition of the α-ketoglutarate-dependent dioxygenases and consequently to histone hypermethylation [206].…”

Section: Therapeutic Opportunities Of Cancer Metabolismmentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

104

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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“…IDH1 and IDH2 are NADP-dependent isocitrate dehydrogenases that catalyze isocitrate to a-KG in TCA cycle, and the subcellular localizations are in cytosol and mitochondria, respectively [70]. IDH1/2 mutations are detected in 15-33 % of AML mostly in normal karyotype-AML, 3.5 % of MDS, 2-5 % of MPN, and also in glioma and multiple endochondromatosis [70][71][72][73][74].…”

Section: Idh1/2mentioning

confidence: 99%

Gene mutations of acute myeloid leukemia in the genome era

Naoe

Kiyoi

2013

Int J Hematol

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Ten years ago, gene mutations found in acute myeloid leukemia (AML) were conceptually grouped into class I mutation, which causes constitutive activation of intracellular signals that contribute to the growth and survival, and class II mutation, which blocks differentiation and/or enhance self-renewal by altered transcription factors. A cooperative model between two classes of mutations has been suggested by murine experiments and partly supported by epidemiological findings. In the last 5 years, comprehensive genomic analysis proceeded to find new gene mutations, which are found in the epigenome-associated enzymes and the molecules never noticed so far. These new mutations apparently increase the complexity and heterogeneity of AML. Although a long list of gene mutations might have been compiled, the entire picture of molecular pathogenesis in AML remains to be elucidated because gene rearrangement, gene copy number, DNA methylation and expression profiles are not fully studied in conjunction with gene mutations. Comprehensive genome research will deepen the understanding of AML to promote the development of new classification and treatment. This review focuses on gene mutations that were recently discovered by genome sequencing.

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IDH mutations in glioma and acute myeloid leukemia

Cited by 324 publications

References 81 publications

Transketolase counteracts oxidative stress to drive cancer development

Transketolase counteracts oxidative stress to drive cancer development

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Gene mutations of acute myeloid leukemia in the genome era

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