IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 07/2010; 24(7):1302-9. DOI: 10.1038/leu.2010.113
Source: PubMed


In a multi-institutional collaborative project, 1473 patients with myeloproliferative neoplasms (MPN) were screened for isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations: 594 essential thrombocythemia (ET), 421 polycythemia vera (PV), 312 primary myelofibrosis (PMF), 95 post-PV/ET MF and 51 blast-phase MPN. A total of 38 IDH mutations (18 IDH1-R132, 19 IDH2-R140 and 1 IDH2-R172) were detected: 5 (0.8%) ET, 8 (1.9%) PV, 13 (4.2%) PMF, 1 (1%) post-PV/ET MF and 11 (21.6%) blast-phase MPN (P<0.01). Mutant IDH was documented in the presence or absence of JAK2, MPL and TET2 mutations, with similar mutational frequencies. However, IDH-mutated patients were more likely to be nullizygous for JAK2 46/1 haplotype, especially in PMF (P=0.04), and less likely to display complex karyotype, in blast-phase disease (P<0.01). In chronic-phase PMF, JAK2 46/1 haplotype nullizygosity (P<0.01; hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7-5.2), but not IDH mutational status (P=0.55; HR 1.3, 95% CI 0.5-3.4), had an adverse effect on survival. This was confirmed by multivariable analysis. In contrast, in both blast-phase PMF (P=0.04) and blast-phase MPN (P=0.01), the presence of an IDH mutation predicted worse survival. The current study clarifies disease- and stage-specific IDH mutation incidence and prognostic relevance in MPN and provides additional evidence for the biological effect of distinct JAK2 haplotypes.


Available from: Terra Lasho, Aug 07, 2014
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    • "8/277 (2.9) 26/277 (9.4) ND ND ND ND Pardanani A. et al. [25] 5/200 (2.5) 4/200 (2) ND ND ND ND Tefferi A. et al. [7] 10/1327 (0.8) 16/1327 (1.2 "
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    ABSTRACT: Mutations of isocitrate dehydrogenase isoform 1 and 2 (IDH1 and IDH2) genes have been identified in glioblastoma and acute myeloid leukemia (AML). However, little is known about the molecular alterations of IDH genes in preleukemic disorders with a propensity to transform to AML. We performed polymerase chain reaction-denaturing high performance liquid chromatography (PCR-DHPLC) followed by direct sequencing to detect IDH mutations in 237 patients with myeloproliferative neoplasms (MPNs; n=108), myelodysplastic syndrome (MDS; n=22), paroxysmal nocturnal hemoglobinuria (PNH; n=41), and aplastic anemia (AA; n=66). No IDH1 R132 and IDH2 R172 mutations were identified in the entire cohort, whereas IDH1 G105G allele was detected in 4/108 MPN (3.70%), 2/22 MDS (9.09%), and 2/41 PNH (4.88%) patients. Three IDH2 R140Q mutations were found in 2/108 MPN (1.85%) and 1/22 MDS (4.54%) patients, while one IDH2 G145G allele was found in 0.92% (1/108) of MPN patients. Overall, our data suggest that IDH mutations are rare in the preleukemic disorders and may not be the major initial step in AML leukemogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.
    Blood Cells Molecules and Diseases 11/2014; 54(3). DOI:10.1016/j.bcmd.2014.11.017 · 2.65 Impact Factor
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    • "However, despite significant insight into the role of specific mutations, including the JAK2V617F mutation, the precise mechanisms in MPN remain elusive. It is very likely that additional mutations in MPN will be described soon, but practical relevance in terms of either disease prognostication or value as drug targets has so far been limited [42]. "
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    ABSTRACT: Since the discovery of JAK2V617F tyrosine kinase-activating mutation, several genes have been found mutated in myeloproliferative neoplasms (MPNs). FLT3-ITD, NPM1, and DNMT3A mutations frequently occurred in AML patients and have been found conferred with myeloproliferative neoplasms in mouse model. Therefore, we sought to search for mutations in JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in 129 cases including 120 classic MPN cases and 9 MDS/MPN cases. JAK2V617F mutation was found in 60% of the 120 classic MPNs. However, none of the patients displayed FLT3-ITD and NPM1 mutations; only 2 patients harbored DNMT3A R882 mutation. Further studies including whole-genome sequence will be conducted to investigate the possible involvement of these genes in MPN.
    BioMed Research International 05/2014; 2014:485645. DOI:10.1155/2014/485645 · 1.58 Impact Factor
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    • "Subsequent analyzes on a large number of AML patients treated on multiple clinical protocols confirmed the presence of IDH1 R132 mutations and also identified IDH2 R140 and IDH2 R172 mutations in ∼20% of adult-onset AML with normal cytogenetics (Mardis et al., 2009; Abbas et al., 2010; Boissel et al., 2010; Green et al., 2010; Gross et al., 2010; Ho et al., 2010; Marcucci et al., 2010; Paschka et al., 2010; Schnittger et al., 2010; Thol et al., 2010a). These mutations also have been identified, albeit at much lower frequency, in myelodysplastic syndromes and myeloproliferative neoplasms (Abbas et al., 2010; Green and Beer, 2010; Paschka et al., 2010; Tefferi et al., 2010; Thol et al., 2010b). Recently, a number of other tumors have been identified to harbor IDH mutations including angioimmunoblastic T-cell lymphoma (Cairns et al., 2012), chondrosarcoma (Amary et al., 2011), and intrahepatic cholangiocarcinoma (Borger et al., 2012; Wang et al., 2012). "
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    ABSTRACT: Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II-III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of α-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2HG is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alterations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential molecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics.
    Frontiers in Oncology 07/2013; 3:169. DOI:10.3389/fonc.2013.00169
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