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 n8; IDH2 R140 n10) and the minor allele of single-nucleotide polymorphism (SNP) rs11554137 in 47 children (10.2%). IDH mutations were associated with an intermediate age (P0.008), FAB M1/M2 (P0.013) and nucleophosmin1 mutations (P0.001). In univariate analysis, IDHmutatedcompared with IDHwildtypepatients 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 (P0.62) compared with major allele patients. Gene expression profiles of 12 IDHmutatedwere compared with 201 IDHwildtypepatients 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 IDH mutated cases.

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Keywords AML, IDH1, IDH2, mutation, pediatric, prognostication
Persistent URL dx.doi.org/10.1038/leu.2011.142, hdl.handle.net/1765/33931
Citation
Damm, F., Thol, F., Hollink, I.H.I.M., Zimmermann, M., Reinhardt, K., van den Heuvel-Eibrink, M.M., … Thiede, C.. (2011). Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: A study of the AML-BFM and DCOG study groups. Leukemia, 25(11), 1704–1710. doi:10.1038/leu.2011.142