Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML

Chaturvedi, Anuhar; Cruz, Michelle; Jyotsana, Nidhi; Sharma, Amit; Yun, Haiyang; Görlich, Kerstin; Wichmann, Manfred; Schwarzer, Adrian; Preller, Matthias; Thol, Felicitas; Meyer, Johann; Haemmerle, Reinhard; Struys, Eduard A.; Jansen, Erwin E.W.; Modlich, Ute; Li, Zhixiong; Sly, Laura M.; Geffers, Robert; Lindner, Robert; Manstein, Dietmar J.; Lehmann, Ulrich; Krauter, Jürgen; Ganser, Arnold; Heuser, Michael

doi:10.1182/blood-2013-03-491571

Cited by 189 publications

(164 citation statements)

References 46 publications

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“…13e20, 33,34 With the use of a sensitive NGS mutation panel, we identified dual mutations in IDH1 and IDH2 that occur at greater frequency than previously described. Among the IDH-mutated myeloid neoplasms (n Z 21), nearly onequarter were found to have dual IDH mutations (5 of 21 patients, including one patient who harbored two IDH2 mutations.)…”

Section: Dual Idh1/2 Mutations In Aml and Mdsmentioning

confidence: 87%

Detection of Dual IDH1 and IDH2 Mutations by Targeted Next-Generation Sequencing in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Platt

Fathi

Borger

et al. 2015

The Journal of Molecular Diagnostics

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Studies in myeloid neoplasms have described recurrent IDH1 and IDH2 mutations as primarily mutually exclusive. Over a 6-month period of clinical testing with a targeted next-generation sequencing assay, we evaluated 92 patients with acute myeloid leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia and identified a subset of 21 patients (23%) who harbored mutations in either IDH1 or IDH2. Of the 21 patients with IDH mutations, 4 (19%) were found to have single nucleotide variants in both IDH1 and IDH2. An additional patient included in the study was found to have two different IDH2 mutations. The mutations were typically present at different variant allelic frequencies, with one predominating over the other, consistent with the presence of multiple subclones in a single patient. In one case, the variant allelic frequencies in both IDH1 and IDH2 were equally low in the setting of a high percentage of blasts, suggesting that the IDH mutations were unlikely to be present in the founding clone. Given these data, we conclude that dual IDH1/2 mutations likely were previously underestimated, a finding that may carry important treatment implications. (J Mol Diagn 2015, 17: 661e668; http://dx.doi.org/10.1016/j.jmoldx.2015 In recent years, whole-genome sequencing of acute myeloid leukemias (AMLs) led to the identification of frequent heterozygous mutations in isocitrate dehydrogenase 1 gene (IDH1).1,2 Subsequent exome sequencing and targeted resequencing studies in AML also identified frequent IDH2 mutations. 3,4 Overall, approximately 15% to 30% of AML have mutations in IDH1 or IDH2, almost exclusively at codon Arg132 for IDH1 and at codons Arg140 and Arg172 for IDH2.1,3e6 Patients with cytogenetically normal AML are enriched for these mutations. The mutations confer neomorphic enzyme activity through the NADPH-dependent reduction of the normal end-product a-ketoglutarate to the putative oncometabolite 2-hydroxyglutarate. The accumulation of high levels of 2-hydroxyglutarate in the IDH1/2-mutant tumor provides an important mechanism of cellular transformation through the targeting of epigenetic regulators. 7IDH mutations were also identified in preleukemic clonal malignancies, including myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms (approximately 5% of MDS/myeloproliferative neoplasm and approximately 20% of AML arising from MDS or myeloproliferative neoplasm).

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Section: Dual Idh1/2 Mutations In Aml and Mdsmentioning

confidence: 87%

Detection of Dual IDH1 and IDH2 Mutations by Targeted Next-Generation Sequencing in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Platt

Fathi

Borger

et al. 2015

The Journal of Molecular Diagnostics

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“…A single hit, which is both loss of function and gain of function, is only ever observed in these genes. In both gliomas and AML, mutations in IDH genes have been suggested as a very early, and perhaps founder mutations, although in neither disease does IDH mutation appear to be able to induce transformation on its own 55, 56, 57, 58. What is common to all three genes is that they are either situated directly within the mitochondrial matrix ( SDH , FH , and IDH2 ) or their metabolic activity directly affects that of the mitochondrion ( IDH1 ).…”

Section: Mutations Of Mitochondrial (And Associated) Metabolic Enzymementioning

confidence: 99%

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Hollinshead

Tennant

2016

WIREs Mechanisms of Disease

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Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia‐induced changes in the proteome mediated by the activity of transcription factors such as hypoxia‐inducible factor 1. Hypoxia is a well‐described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer‐associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272–285. doi: 10.1002/wsbm.1334For further resources related to this article, please visit the WIREs website.

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“…This chemical reaction occurs at low levels under normal conditions with wild-type IDH enzymes but is greatly enhanced in cells with mutant forms of IDH1 and IDH2. This is biologically relevant since high serum 2-HG is present in both mouse models of IDHm enzymes [18][19][20] and in IDH1m and IDH2m AML patients [21].…”

Section: Mutant Isocitrate Dehydrogenase Enzymes In Malignant Disordersmentioning

confidence: 99%

“…The malignant phenotype was reversible in the majority of mice upon withdrawal of doxycycline, as manifested by elimination of leukemia blast cells and normal hematopoiesis restoration. Similarly, while Hoxa9 expression alone resulted in a latent myeloproliferative disorder without leukemic transformation in mice [70], co-expression of IDH1 R132C in Hoxa9 immortalized mouse bone marrow cells resulted in a short-latency myeloproliferative disorder [19]. Flt3-ITD transgenic mice also develop a myeloproliferative neoplasm but not acute leukemia [71].…”

Section: Idhm Cooperate With Other Oncogenes To Induce Leukemogenic Tmentioning

confidence: 99%

Mutant IDH : A Targetable Driver of Leukemic Phenotypes Linking Metabolism, Epigenetics and Transcriptional Regulation

Garrett-Bakelman

Melnick

2016

Epigenomics

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Aberrant epigenomic programming is a hallmark of acute myeloid leukemia. This is partially due to somatic mutations that perturb cytosine methylation, histone posttranslational modifications and transcription factors. Remarkably, mutations in the IDH1 and IDH2 genes perturb the epigenome through all three of these mechanisms. Mutant IDH enzymes produce high levels of the oncometabolite (R)-2-hydroxyglutarate that competitively inhibits dioxygenase enzymes that modify methylcytosine to hydroxymethylcytosine and histone tail methylation. The development of IDH mutant specific inhibitors may now enable the therapeutic reprogramming of both layers of the epigenome spontaneously to revert the malignant phenotype of these leukemias and improve clinical outcome for acute myeloid leukemia patients with IDH mutations.

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Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML

Cited by 189 publications

References 46 publications

Detection of Dual IDH1 and IDH2 Mutations by Targeted Next-Generation Sequencing in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Detection of Dual IDH1 and IDH2 Mutations by Targeted Next-Generation Sequencing in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Mutant IDH : A Targetable Driver of Leukemic Phenotypes Linking Metabolism, Epigenetics and Transcriptional Regulation

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