Type and location of isocitrate dehydrogenase mutations influence clinical characteristics and disease outcome of acute myeloid leukemia

Koszarska, Magdalena; Bors, András; Feczko, Angela; Meggyesi, Nóra; Bátai, Árpád; Csomor, Judit; Ádám, Emma; Kozma, András; Orbán, Tamás I.; Lovas, Nóra; Sipos, Andrea; Karászi, Éva; Dolgos, János; Fekete, S.; Reichardt, Juergen K.V.; Lehoczky, Eniko; Masszi, Tamás; Tordai, Attila; Andrikovics, Hajnalka

doi:10.3109/10428194.2012.736981

Cited by 26 publications

(22 citation statements)

References 45 publications

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“…In cholangiocarcinomas and chondrosarcomas, IDH1 Arg132 mutations are also far more common than IDH2 Arg172 mutations, although the IDH1 mutations in these tumors most often result in an arginine-tocysteine substitution (IDH1 R132C) (Amary et al 2011a;Arai et al 2012;Borger et al 2012). This is in contrast to AML, where IDH1 and IDH2 mutations occur at similar frequencies (Abbas et al 2010;Marcucci et al 2010;Paschka et al 2010;Koszarska et al 2012). The single most common IDH mutation in AML is the replacement of Arg140 of IDH2 with a glutamine (IDH2 R140Q).…”

Section: Idh Mutations In Human Cancermentioning

confidence: 43%

“…The most frequent alleles are indicated in bold. The results outlined are from meta analyses (Chang et al 2011) and studies that included large numbers of patients (Abbas et al 2010;Marcucci et al 2010;Paschka et al 2010;Amary et al 2011a;Pansuriya et al 2011;Pusch et al 2011;Arai et al 2012;Borger et al 2012;Cairns et al 2012;Koszarska et al 2012).…”

Section: Idh Mutations In Human Cancermentioning

confidence: 99%

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What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

2013

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Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similarHere we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.Cellular metabolism has been hypothesized to play a central role in cancer since the observation made almost a century ago by Otto Warburg (Warburg 1956) that cancer cells preferentially generate energy by metabolizing glucose to lactate. Even in the presence of oxygen, cancer cells switch from generating ATP by the highly energy-efficient process of oxidative phosphorylation to the much less efficient process of glycolysis (Vander Heiden et al. 2009;Dang 2012). Why this switch occurs has long been a mystery, although the observation that normal cells use ''aerobic glycolysis'' during periods of increased proliferation supports the hypothesis that this metabolic switch is an important feature of rapidly dividing cells (Locasale and Cantley 2011;Lunt and Vander Heiden 2011). Recent work suggests that aerobic glycolysis facilitates cellular transformation by producing the high levels of glycolytic intermediates that proliferating cells need for the biosynthesis of lipids, amino acids, and nucleic acids. Moreover, metabolic reprogramming appears to be sufficient to mediate tumorigenesis in some systems (Lyssiotis and Cantley 2012;Sebastian et al. 2012). Nevertheless, whether altered cellular metabolism is a cause of cancer or merely an adaptive response of cancer cells in the face of accelerated cell proliferation is still a topic of some debate.The recent identification of cancer-associated mutations in three metabolic enzymes suggests that altered cellular metabolism can indeed be a cause of some cancers (Pollard et al. 2003;King et al. 2006;Raimundo et al. 2011). Two of these enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are bone fide tumor suppressors, and loss-of-function mutations in FH and SDH have been identified in various cancers, including renal cell carcinomas and paragangliomas. The third mutated enzyme, isocitrate dehydrogenase (IDH), is a more complicated case. Mutations in two isoforms of IDH, IDH1 and IDH2, are common in a diverse array of cancers, including gliomas and acute myelogenous leukemia (AML) (Dang et al. 2010). The mutant enzymes are not catalytically inactive. Rather, the cancer-associated mutations alter the catalytic activity of the enzymes such that they produce high levels of a metabolite, (R)-2-hydroxyglutarate [(R)-2HG], which is normally ...

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Section: Idh Mutations In Human Cancermentioning

confidence: 43%

Section: Idh Mutations In Human Cancermentioning

confidence: 99%

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

2013

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“…As shown in Supplementary Table S1, IDH gene aberrations were closely associated with elderly patients in 12 studies (16, 18, 25, 26, 30, 32, 33, 38, 41-43, 47, 48) and with higher platelet count in 9 studies (16,18,26,27,29,36,38,42,43). In addition, in the aspect of FAB classification, patients with M1 harbored higher percentage of IDH mutations (6,17,18,24,25,29,30,39,42), whereas in cases with M4, lower percentage was observed (17,24,29,47).…”

Section: Study Characteristicsmentioning

confidence: 96%

Correlation Between Isocitrate Dehydrogenase Gene Aberrations and Prognosis of Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

et al. 2017

Clinical Cancer Research

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Purpose: Whether isocitrate dehydrogenase (IDH) gene aberrations affected prognosis of patients with acute myeloid leukemia (AML) was controversial. Here, we conducted a meta-analysis to evaluate their prognostic value.Experimental Design: PubMed, Embase, Cochrane, and Chinese databases were searched to identify studies exploring how IDH gene aberrations affected AML outcome. Pooled HRs and relative risks (RR) were calculated, along with 95% confidence intervals (CI).Results: Thirty-three reports were included.

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“…Similarly, R132K IDH1 is homologous to R172K IDH2, the second most common IDH2 mutation identified in AML (50). Thus the relative catalytic inefficiency of D2HG production by R132K IDH1 (Table 4) was also surprising.…”

Section: ␣Kg To D2hg Catalyzed By Idh1mentioning

confidence: 99%

Molecular mechanisms of isocitrate dehydrogenase 1 (IDH1) mutations identified in tumors: The role of size and hydrophobicity at residue 132 on catalytic efficiency

Matteo

Grunseth

Gonzalez

et al. 2017

Journal of Biological Chemistry

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Edited by John M. Denu Isocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP؉ -dependent conversion of isocitrate (ICT) to ␣-ketoglutarate (␣KG) in the cytosol and peroxisomes. Mutations in IDH1 have been implicated in >80% of lower grade gliomas and secondary glioblastomas and primarily affect residue 132, which helps coordinate substrate binding. However, other mutations found in the active site have also been identified in tumors. IDH1 mutations typically result in a loss of catalytic activity, but many also can catalyze a new reaction, the NADPH-dependent reduction of ␣KG to D-2-hydroxyglutarate (D2HG). D2HG is a proposed oncometabolite that can competitively inhibit ␣KG-dependent enzymes. Some kinetic parameters have been reported for several IDH1 mutations, and there is evidence that mutant IDH1 enzymes vary widely in their ability to produce D2HG. We report that most IDH1 mutations identified in tumors are severely deficient in catalyzing the normal oxidation reaction, but that D2HG production efficiency varies among mutant enzymes up to ϳ640-fold. Common IDH1 mutations have moderate catalytic efficiencies for D2HG production, whereas rarer mutations exhibit either very low or very high efficiencies. We then designed a series of experimental IDH1 mutants to understand the features that support D2HG production. We show that this new catalytic activity observed in tumors is supported by mutations at residue 132 that have a smaller van der Waals volume and are more hydrophobic. We report that one mutation can support both the normal and neomorphic reactions. These studies illuminate catalytic features of mutations found in the majority of patients with lower grade gliomas.Metabolic changes in tumors have been described for nearly a century (1-3), but only relatively recently have enzymes involved in metabolic processes been established as tumor suppressors or oncoproteins. One of the more striking examples of metabolic enzymes playing a role in tumorigenesis includes isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2).3 These homodimeric enzymes are responsible for the reversible NADP ϩ -and Mg 2ϩ -dependent conversion of ICT to ␣KG (Fig. 1A) in the cytosol and peroxisomes (IDH1), or mitochondria (IDH2). IDH3 is responsible for the same reaction within the context of the TCA cycle, although the oxidative decarboxylation catalyzed by this enzyme is non-reversible and NAD ϩ -dependent. Mutations in IDH1 and IDH2 were identified in glioblastoma multiforme in a large sequencing effort (4), and soon Ͼ80% of adult grade II/III gliomas and secondary glioblastomas were found to have IDH1 mutations, commonly R132H or R132C IDH1 (5, 6) (reviewed in Refs. 7-9). Subsequently ϳ10 -20% of acute myeloid leukemias were shown to have primarily IDH2 mutations, typically R140Q or R172K IDH2 (10). Early mechanisms of tumorigenesis focused on deficient conversion of ICT to ␣KG (11), suggesting that IDH serves as a tumor suppressor, in part through altering levels of hypoxia-inducible transcription factor-1␣ (12). However,...

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Type and location of isocitrate dehydrogenase mutations influence clinical characteristics and disease outcome of acute myeloid leukemia

Cited by 26 publications

References 45 publications

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

Correlation Between Isocitrate Dehydrogenase Gene Aberrations and Prognosis of Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

Molecular mechanisms of isocitrate dehydrogenase 1 (IDH1) mutations identified in tumors: The role of size and hydrophobicity at residue 132 on catalytic efficiency

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