Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML-BFM and DCOG study groups
Menée à partir d'échantillons tumoraux prélevés sur 460 patients pédiatriques atteints de leucémie myéloïde aiguë, cette étude évalue la prévalence et la valeur pronostique de mutations des gènes IDH1 et IDH2
Mutations in the NADP+-dependent isocitrate dehydrogenase genes 1 and 2 (IDH1 and IDH2) have recently been found in adult acute myeloid leukemia (AML) patients with a prevalence rising up to 33%. To investigate the frequency of IDH1/2 mutations in pediatric AML, we characterized the mutational hotspot (exon 4) of these genes in diagnostic samples from 460 pediatric AML patients. Our analysis identified somatic IDH1/2 mutations in 4% of cases (IDH1 R132 n=8; IDH2 R140 n=10) and the minor allele of single-nucleotide polymorphism (SNP) rs11554137 in 47 children (10.2%). IDH mutations were associated with an intermediate age (P=0.008), FAB M1/M2 (P=0.013) and nucleophosmin1 mutations (P=0.001). In univariate analysis, IDHmutated compared with IDHwildtype patients showed a significantly improved overall survival (OS; P=0.032) but not event-free survival (EFS; P=0.14). However, multivariate analysis did not show independent prognostic significance. Children with at least one minor allele of IDH1 SNP rs11554137 had similar EFS (P=0.27) and OS (P=0.62) compared with major allele patients. Gene expression profiles of 12 IDHmutated were compared with 201 IDHwildtype patients to identify differentially expressed genes and pathways. Although only a small number of discriminating genes were identified, analysis revealed a deregulated tryptophan metabolism, and a significant downregulation of KYNU expression in IDHmutated cases.
Leukemia , résumé, 2010