Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients

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.

Molecular Evaluation of DNMT3A and IDH1/2 Gene Mutation: Frequency, Distribution Pattern and Associations with Additional Molecular Markers in Normal Karyotype Indian Acute Myeloid Leukemia Patients

“…Most reports of DNMT3A and IDH mutations come from Western countries, while there are few reports from Asia (Zou et al, 2010;Chotirat et al, 2012;Hou et al, 2012). At the present time, no precise published data exist in India with respect to the frequency and distribution patterns of DNMT3A and IDH mutations, despite the fact that AML is one of the most common hematologic malignancies associated with the greatest mortality and morbidity in this country.…”

“…The outcome of such advanced studies has led to the identification of DNA methyltransferase 3a (DNMT3A) mutations (Ley et al, 2010), ten-eleven-translocation oncogene family member 2 (TET2) (Delhommeau et al, 2009), and mutations and isocitrate dehydrogenase (IDH) 1 gene mutations (Mardis et al, 2009) in AML patients. Of these mutations, two markers viz., DNMT3A and IDH mutations have gained tremendous attention in recent times, and have been extensively evaluated by different research groups across the globe (Paschka et al, 2010;Thol et al, 2011;Chotirat et al, 2012;Marcucci et al, 2012).…”

New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance

“…35 The dedifferentiated CS cell line CH03 did not show any IDH1 or IDH2 mutations, but presented a deletion in TP53-coding sequence (Figure 2b). Note that the sequence of TP53 could present some smaller peaks corresponding to minor amplicons generated by alternative splicing.…”

Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

“…IDH1 gene is reside on chromosome band 2q33.3 and its product is NADP-dependent and localized in cytoplasm and peroxisomes while IDH2 gene is located at chromosome band 15q26.1 and encodes the mitochondrial NADP-dependent IDH2 enzyme [132]. Recurring mutations either in IDH1 and IDH2 were present in more than 70% of WHO grade 2 and 3 astrocytomas, oligodendrogliomas, and glioblastomas and in approximately 30% of patients with CN-AML [133]. Both IDH1/2 mutants cause loss of the physiologic enzyme function and create a novel ability of the enzymes to convert α-ketoglutarate into 2-hydroxyglutarate, a putative oncometabolite [134].…”