Abstract
BackgroundIsocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to α-ketoglutarate. Acquired somatic mutations of IDH1 and IDH2 have recently been reported in some types of brain tumors and a small proportion of acute myeloid leukemia (AML) cases.MethodsTwo-hundred and thirty newly diagnosed AML patients were analyzed for the presence of IDH1 and IDH2 heterozygous mutations by polymerase chain reaction-denaturing high performance liquid chromatography (PCR-DHPLC) followed by direct sequencing. Clinical and biological characteristics were analyzed and correlated to the IDH mutational status. Coexisting mutations such as FLT3, PML-RARA, RAS, AML1, and NPM1 mutations were additionally explored.ResultsThe prevalence of IDH1 and IDH2 mutations was 8.7% (20/230) and 10.4% (24/230), respectively. Six missense mutations were identified among IDH1-mutated cases; p.R132H (n = 8), p.R132C (n = 6), p.R132S (n = 2), p.R132G (n = 2), p.R132L (n = 1), and p.I99M (n = 1). Two missense mutations were found in IDH2-mutated cases; p.R140Q (n = 20) and p.R172K (n = 4). No patients had dual IDH1 and IDH2 mutations. About 18% of AML with normal cytogenetics and 31% of acute promyelocytic leukemia had IDH mutations. Half of the IDH-mutated cohort had normal karyotype and the major FAB subtype was AML-M2. Interestingly, IDH1- and IDH2-mutated cases predominantly had NPM1 mutations (60-74%) as compared to the wild type (P < 0.001). Very few IDH-mutated cases had FLT3 and/or RAS abnormalities and none of them had AML1 mutations. Older age and higher median platelet counts were significantly associated with IDH2 mutations although the clinical impact of either IDH1 or IDH2 mutations on patients' overall survival could not be observed.ConclusionOverall, 19% of newly diagnosed AML patients had alterations of IDH genes. No patients concurrently carried both IDH1 and IDH2 mutations suggesting that these mutations were mutually exclusive. NPM1 mutation appears as a major coexisting genetic mutation in IDH-mutated patients. Our present data failed to support the prognostic relevance of IDH mutations although alterations of these metabolic genes potentially have an important role in leukemia development.
Highlights
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to a-ketoglutarate
In 2009, IDH1 mutation was reported in a subset of acute myeloid leukemia (AML) patients lacking specific chromosomal aberrations [5] and in 2010, IDH2 mutation was identified in AML, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN) [15,16,17]
The worldwide frequencies of IDH1 and IDH2 mutations in newly diagnosed AML patients range from 2% to 14% and 1% to 19%, respectively, with the mutations mostly restricted to codon R132 of IDH1 and codon R140 of IDH2 [5,15,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]
Summary
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to a-ketoglutarate. 4050% of AML cases do not carry any detectable chromosomal abnormalities, a fraction of them are found to have mutations of genes that normally function in cell proliferation, differentiation, and survival such as FLT3, NPM1, RAS, WT1, and AML1 [3,4]. Isocitrate dehydrogenase (IDH) is one the enzymes that, if defective, lead to abnormal cellular metabolism [8,9]. Biochemical and molecular analyses reveal that mutations at the evolutionarily conserved site of IDH lead to interruption of the normal ability of enzyme to bind substrates and subsequent acquisition of novel enzymatic activity resulting in a substantial increase of oncometabolite R(-) -2-hydroxyglutarate (2HG) through a-KG conversion [8,19,20]. The accumulation of elevated 2HG induces global DNA hypermethylation and interruption of hematopoietic differentiation [33,34]
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