Acquired somatic mutations affecting the R132 residue of isocitrate dehydrogenase 1 (IDH1) and the R172 residue of IDH2 have been initially described in gliomas, mainly in oligoastrocytic tumors.1 More recently, mutation of the IDH1 gene has been reported in de novo acute myeloid leukemia (AML).2 The prevalence of IDH1 mutations in de novo AML ranges between 5–9% of cases. They are strongly associated with the normal karyotype and are more frequent in patients with NPM1 mutation. IDH1 mutations have no impact on event-free survival in AML patients, except that they have an unfavorable effect on event-free survival in those with intermediate-risk karyotype.3, 4 The fourth exon of both IDH1 and IDH2 genes encodes three arginine residues (R100, R109 and R132 in IDH1 and R140, R149 and R172 in IDH2) that are important for the activity of the proteins.5
Here we have analyzed the sequence of the fourth exon of IDH1 and IDH2 genes established from the bone marrow DNA of 100 cases of myelodysplastic syndrome (MDS) including all subtypes of the WHO 2008 classification, 90 cases of MDS/myeloproliferative neoplasm (MPN), including 88 cases of chronic myelomonocytic leukemia and 2 cases of refractory anemia with ringed sideroblast and thrombocytosis, and 41 cases of AML post-MDS and AML post-MDS/MPN, referred to as secondary AML (sAML). To identify associations between molecular events, we also established the TET2 and JAK2 status of the samples.
Out of 231 cases, mutations in IDH1 or IDH2 genes were identified in 5% (n=5) of MDS, in 8.8% (n=8) of MDS/MPN and in 9.7% (n=4) of sAML cases. The frequencies were not statistically different between the three groups. The characteristics of patients with a mutation in IDH genes are summarized in Table 1. IDH1 and IDH2 mutations were always heterozygous and were mutually exclusive. Among the 17 patients with IDH gene mutations, 11 presented with IDH2 R140Q, 1 with IDH2 R140L, 1 with IDH2 R172K, 2 with IDH1 R132C, 1 with IDH1 R132L and 1 with IDH1 R132G substitution (Figure 1). Mutations preferentially affected the IDH2 gene (n=13) than the IDH1 gene (n=4). Mutations were restricted to IDH2 in MDS/MPN, while IDH1 mutations, all affecting the R132 residue, were observed in early MDS and in sAML.
The evidence for IDH2 substitutions in our series of MDS, MDS/MPN or sAML cases is extended to the recent findings that have reported cases of myeloid disorders with acquired IDH2 R140Q and R172K substitutions.6, 7 Arginine substitutions in both IDH1 and IDH2 are likely gain-of-function mutations that would result in the accumulation of 2-hydroxyglutarate.6 We identified one case of refractory anemia with ringed sideroblast and thrombocytosis harboring a JAK2 V617F mutation together with an IDH2 R140L substitution. IDH2 mutations have been shown to be acquired during the evolution of two cases of JAK2 V617F-positive MPN to AML.7 The JAK2 mutation was no longer detectable in three cases of MPN in the leukemic phase when IDH1 or IDH2 mutations occur, suggesting that those mutations occurred independently.7 Six MDS or MDS/MPN cases were analyzed at early stage and also after leukemic transformation. One of them (Patient 209) demonstrated an IDH2 R172K substitution at both stages, the others being wild type for IDH1, IDH2, TET2 and JAK2 at both stages.
In the present series of MDS and MDS/MPN, IDH gene mutations tended to associate with normal karyotype, although this was not statistically significant (chi-square test, P=0.125). There was no relationship with Hb level, neutrophil count, percentage of bone marrow blasts or IPSS. However, the median platelet count was significantly higher in mutated than in unmutated patients (Wilcoxon's test; P=0.023). Finally, we did not find any impact of IDH gene mutations on overall survival in the group of patients with MDS or MDS/MPN.
IDH mutations are less frequent than TET2 alterations which were detected by sequencing or SNP arrays in 28% of MDS, 48% of MDS/MPN, and 27% of AML post-MDS or MDS/MPN cases (Table 1). Mutations in IDH and TET2 genes coexisted in only four samples (one MDS, two MDS/MPN and one sAML), suggesting that IDH mutations may occur independently of TET2 mutations (chi-square test, n=231; P=0.248).
In conclusion, we have described here mutations of IDH1 and IDH2 genes in early MDS, in MDS/MPN at chronic phase and in sAML. Although these mutations are uncommon in MPN in the chronic phase,7 they are detectable in early MDS or in MDS/MPN in the chronic phase, thus preceding AML transformation. This suggests that IDH mutations, particularly IDH2 mutations, could contribute to the dysplastic phenotype of these diseases.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360: 765–773.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.
Chou WC, Hou HA, Chen CY, Tang JL, Yao M, Tsay W et al. Distinct clinical and biological characteristics in adult acute myeloid leukemia bearing isocitrate dehydrogenase 1 (IDH1) mutation. Blood 2010. e-pub ahead of print 22 January 2010; doi: 10.1182/blood-2009-11-253070.
Schnittger S, Haferlach C, Ulke M, Kaya L, Weiss T, Kern W et al. IDH1 mutations are detected in 9.3% of all AML and are strongly associated with intermediate risk karyotype and unfavourable prognosis: a study of 999 patients. Blood 2009; 114 (abstract LBA-3).
Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem 2004; 279: 33946–33957.
Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 2010; 207: 339–344.
Green A, Beer P . Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med 2010; 362: 369–370.
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–2301.
We thank Professor D Bouscary, Dr J Tamburini and Dr S Park for including the patients. This work was supported by INSERM, INCa and the DRRC (Direction régionale de la Recherche Clinique AP-HP).
The authors declare no conflict of interest.
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Kosmider, O., Gelsi-Boyer, V., Slama, L. et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 24, 1094–1096 (2010). https://doi.org/10.1038/leu.2010.52
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