Prognostic Impact of Isocitrate Dehydrogenase Enzyme Isoforms 1 and 2 Mutations in Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group

Boissel, Nicolas; Nibourel, Olivier; Renneville, Aline; Gardin, Claude; Reman, Oumédaly; Contentin, Nathalie; Bron, Dominique; Pautas, Cécile; Revel, Thierry de; Quesnel, Bruno; Huchette, Pascal; Philippe, N; Geffroy, Sandrine; Terré, Christine; Thomas, Xavier; Castaigné, Sylvie; Dombret, Hervé; Preudhomme, Claude

doi:10.1200/jco.2010.28.2285

Cited by 190 publications

(161 citation statements)

References 30 publications

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“…7,15,17 More perplexingly, IDH2 R172 mutation alone was found to have distinct gene-and microRNA-expression profiles, 9 and appeared to be an independent poor prognostic factor. 18 In contrary, results from two studies suggested a possible favorable impact of IDH2 mutation in subgroups of AML patients. 7,8 Overall, the prognostic implication of IDH2 mutation is still controversial.…”

Section: Introductionmentioning

confidence: 49%

“…7,[13][14][15][16][17] However, different features between IDH1-mutated and IDH2-mutated AML were shown in several reports, and even there existed differences between IDH2 R140 and R172 mutations. 9,17,18 In addition, the prognostic implications of these mutations also varied widely among different institutions. 7,15,17 More perplexingly, IDH2 R172 mutation alone was found to have distinct gene-and microRNA-expression profiles, 9 and appeared to be an independent poor prognostic factor.…”

Section: Introductionmentioning

confidence: 99%

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The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia

et al. 2010

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Although the clinical features of the Isocitrate dehydrogenase 2 (IDH2) mutation in acute myeloid leukemia (AML) have been characterized, its prognostic significance remains controversial and its stability has not been investigated. We analyzed 446 adults with primary non-M3 AML and found IDH2 R172, R140 and IDH1 R132 mutations occurred at a frequency of 2.9, 9.2 and 6.1%, respectively. Compared with wild-type IDH2, mutation of IDH2 was associated with higher platelet counts, intermediate-risk or normal karyotype and isolated þ 8, but was inversely correlated with expression of HLA-DR, CD34, CD15, CD7 and CD56, and was mutually exclusive with WT1 mutation and chromosomal translocations involving core-binding factors. All these correlations became stronger when IDH1 and IDH2 mutations were considered together. Multivariate analysis revealed IDH2 mutation as an independent favorable prognostic factor. IDH2 À /FLT3-ITD þ genotype conferred especially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger age, lower white blood cell count and lactate dehydrogenase level, and was mutually exclusive with NPM1 mutation. Serial analyses of IDH2 mutations at both diagnosis and relapse in 121 patients confirmed high stability of IDH2 mutations. In conclusion, IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis.

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Section: Introductionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia

et al. 2010

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“…Mutations in NPM1, IDH1, and IDH2 were not detected in these patients either, a finding that is consistent with data reported in other studies. 4,[27][28][29][30] The virtual exclusion of mutations in these four genes in patients with a favorable-risk profile is not random and may reflect the leukemogenic properties of the fusion proteins created by these chromosomal rearrangements. The PML-RARA fusion protein, which is created by t(15;17), physically interacts with DNMT3A, and AML-ETO, which is created by t(8;21), interacts with DNMT1; both fusion proteins alter the methylation of specific promoters.…”

Section: Discussionmentioning

confidence: 99%

DNMT3A mutations in acute myeloid leukemia

Shah

Licht

2011

Nat Genet

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“…Data were processed using Genetic Analysis System Software (Beckman Coulter). Other gene mutations, that is, mutations of FLT3 tyrosine kinase domain (FLT3-TKD; FLT3D835/I836), 36 NPM1, 37 CEBPA, 38 WT1 (exons 7 and 9), 39 IDH1R132, 40 IDH2R172, 40 and IDH2R140, 41 were assessed centrally as previously described.…”

Section: Analysis Of Other Gene Mutationsmentioning

confidence: 99%

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

et al. 2012

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Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French --American --British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P ¼ 0.02) and overall survival (5-year OS: 23% vs 45%, P ¼ 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.

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Prognostic Impact of Isocitrate Dehydrogenase Enzyme Isoforms 1 and 2 Mutations in Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group

Abstract: Contrarily to what is reported in gliomas, IDH1m and IDH2m in AML are associated with a poor prognosis. Screening of IDH1m could help to identify high-risk patients within the subset of CN-AML with a favorable genotype.

Cited by 190 publications

References 30 publications

The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia

The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia

DNMT3A mutations in acute myeloid leukemia

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

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