Serum 2-Hydroxyglutarate Production in <i>IDH1</i>- and <i>IDH2</i>-Mutated De Novo Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group

Janin, Maxime; Mylonás, Elena; Saada, Véronique; Micol, Jean-Baptiste; Renneville, Aline; Quivoron, Cyril; Koscielny, Serge; Scourzic, Laurianne; Forget, Sébastien; Pautas, Cécile; Caillot, Denis; Preudhomme, Claude; Dombret, Hervé; Berthon, Céline; Barouki, Robert; Rabier, Daniel; Auger, Nathalie; Griscelli, Frank; Chachaty, Élisabeth; Leclercq, Edwige; Courtier, Marie-Hélène; Bennaceur-Griscelli, Annelise; Solary, Éric; Bernard, Olivier A.; Penard-Lacronique, Virginie; Ottolenghi, Chris; Botton, Stéphane de

doi:10.1200/jco.2013.50.2047

Cited by 108 publications

(96 citation statements)

References 31 publications

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“…It is possible that steroid treatment contributed to a 2HG decrease in this patient, but this effect remains to be confirmed in larger patient series. It is noteworthy that this level of 2HG is significantly lower than the level previously reported in IDH1-or IDH2-mutated AML (median 21 μM, range 2.4-305.6 μM) (26). This discrepancy may be due to a higher tumor burden and proliferation rate in AML compared with AITL.…”

Section: Idh2r172 Mutant Protein Is Expressed In Inducible T-cell Coscontrasting

confidence: 49%

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The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

Lemonnier

Cairns

Inoue

et al. 2016

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

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Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in angioimmunoblastic T-cell lymphoma (AITL), mutations are almost exclusively restricted to IDH2 R172, and levels of 2HG have not been comprehensively measured. In this study, we investigate the expression pattern of mutant IDH2 in the AITL tumor microenvironment and measure levels of 2HG in tissue and serum of AITL patients. We find that mutant IDH2 expression is restricted to the malignant T-cell component of AITL, and that 2HG is elevated in tumor tissue and serum of patients. We also investigate the differences between the three hotspot mutation sites in IDH1 and IDH2 using conditional knock-in mouse models. These studies show that in the lymphoid system, mutations in IDH2 at R172 produce high levels of 2HG compared with mutations at the other two sites and that lymphoid development is impaired in these animals. These data provide evidence that IDH2 R172 mutations may be the only variants present in AITL because of their capacity to produce significant amounts of the oncometabolite 2HG in the cell of origin of this disease.isocitrate dehydrogenase | AITL | lymphoma | 2-hydroxyglutarate | T cell

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Section: Idh2r172 Mutant Protein Is Expressed In Inducible T-cell Coscontrasting

confidence: 49%

“…These findings also suggest that 2HG production persists during malignant progression, and that it could be a useful diagnostic marker. The usefulness of 2HG to monitor minimal residual disease, as it is beginning to be used in AML (26), remains to be determined in further longitudinal studies.…”

Section: Discussionmentioning

confidence: 99%

The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

Lemonnier

Cairns

Inoue

et al. 2016

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

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“…Unlike gliomas, in which the incidence of IDH1 mutations is more frequent than IDH2 mutations, the frequency of IDH1 and IDH2 mutations is similar in patients with AML [9]. Various studies have analyzed 2HG levels, demonstrating that IDH1/2 mutant AML cells and sera have increased levels of 2HG [10,11].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Value of Plasma and Urinary 2-Hydroxyglutarate to Identify Patients With Isocitrate Dehydrogenase-Mutated Glioma

Lombardi

Corona²,

Bellu

et al. 2015

The Oncologist

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Background. Mutant isocitrate dehydrogenase (IDH) 1/2 enzymes can convert a-ketoglutarate into 2-hydroxyglutarate (2HG). The aim of the present study was to explore whether 2HG in plasma and urine could predict the presence of IDH1/2 mutations in patients with glioma. Materials and Methods. All patients had histological confirmation of glioma and a recent brain magnetic resonance imaging scan showing the neoplastic lesion. Plasma and urine samples were taken from all patients, and the 2HG concentrations were determined using liquid chromatography tandem mass spectrometry. Results. A total of 84 patients were enrolled: 38 with R132H-IDH1 mutatedand46with wild type.Among the38patients with mutant IDH1, 21 had high-grade glioma and 17 had low-grade glioma. Among the 46 patients with IDH1 wild-type glioma, 35 and 11 had high-and low-grade glioma, respectively. In all

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“…Different point mutation have been described in AML but all result in the acquisition of a novel metabolic function, leading to the production of 2-hydroxyglutarate (instead of ketoglutarate), deregulating the normal TET2 function. As a consequence the plasmatic levels of 2 hydroxyglutarate has recently been proposed as an alternative tool to the direct sequencing [105]. The real prognostic impact is still a matter of debate.…”

Section: Isocitrate Dehydrogenase 1 and 2 Mutations (Idh1/idh2)mentioning

confidence: 99%

“…They have also been shown to be mutually exclusive of NPM1 mutations and have an inverse association with FLT3-ITD mutations [23,104]. ASXL1 mutations, when present, confer a worse prognosis; several series have demonstrated lower complete remission rates, EFS and OS in patients with these mutations [23, [102][103][104][105], and, as such, they have been shown to be an independent prognostic factor for overall survival.…”

Section: Additional Sex-comb Like 1 (Asxl1)mentioning

confidence: 99%

The Impact of Molecular Genetic in Acute Myeloid Leukemias

Patriarca¹,

Salutari²,

S³

2015

J Blood Disord Transfus

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The discovery and application of advanced molecular techniques, such as gene and microRNA expression profiling, whole genome and exome sequencing and methylation assays, allowed for the identification of recurrent molecular abnormalities in acute myeloid leukemia (AML) that have revolutionized our understanding of the genetic landscape of the disease. Moreover, these modalities have emerged as valuable tools that permit a more comprehensive and detailed molecular characterization of AML, helping in the prediction of prognosis, particularly within the context of cytogenetically normal AML (CN-AML). This review will discuss the major techniques and platforms that have been used to identify novel recurrent gene mutations in AML and briefly describe how these discoveries have impacted on outcome prediction.

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Serum 2-Hydroxyglutarate Production in IDH1- and IDH2-Mutated De Novo Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group

Abstract: Serum 2-HG is a predictor of the presence of IDH1/2 mutations and outcome in these patients. Discrimination between D/L stereoisomers improved specificity.

Cited by 108 publications

References 31 publications

The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development

Diagnostic Value of Plasma and Urinary 2-Hydroxyglutarate to Identify Patients With Isocitrate Dehydrogenase-Mutated Glioma

The Impact of Molecular Genetic in Acute Myeloid Leukemias

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