Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: A study of the AML-BFM and DCOG study groups

F. Damm, F. Thol, I. Hollink, M. Zimmermann, K. Reinhardt, M. M. Van Den Heuvel-Eibrink, C. M. Zwaan, V. De Haas, U. Creutzig, J. H. Klusmann, J. Krauter, M. Heuser, A. Ganser, D. Reinhardt, C. Thiede

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68 Citaten (Scopus)

Samenvatting

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, IDHmutated compared with IDH wildtype 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 (P0.62) 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 IDH mutated cases.

Originele taal-2Engels
Pagina's (van-tot)1704-1710
Aantal pagina's7
TijdschriftLeukemia
Volume25
Nummer van het tijdschrift11
DOI's
StatusGepubliceerd - nov. 2011
Extern gepubliceerdJa

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