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Acute Leukemias

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

Leukemia volume 25, pages 1704–1710 (2011)Cite this article

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Abstract

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.

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Acknowledgements

We are indebted to all patients and the members of the AML–BFM and DCOG study groups for providing leukemia specimens. This study was supported by Grant No.109686 of the Deutsche Krebshilfe–Dr Mildred Scheel Cancer Foundation and HiLF grant 2010 awarded to FD, Schlag-Stiftung to FT, and BMBF Grant 01GS0872 to CT.

Author contributions

FD, FT, IH, DR and CT designed the research; FD, FT, IH, and CT performed the research; KR, DR, JHK, VdH, MMH-E, CMZ, and UC contributed patient samples and clinical data; FD, MZ, IH, DR and CT analyzed the data; FD, FT, IH and CT wrote the paper. All authors read and agreed to the final version of the manuscript.

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Author notes

  1. F Damm, F Thol and I Hollink: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    F Damm, F Thol, J Krauter, M Heuser & A Ganser

  2. Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands

    I Hollink, M M van den Heuvel-Eibrink & C M Zwaan

  3. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    M Zimmermann, K Reinhardt, J-H Klusmann & D Reinhardt

  4. Dutch Childhood Oncology Group, Den Haag, The Netherlands

    V de Haas

  5. Children's Hospital, Pediatric Hematology/Oncology, University of Münster, Münster, Germany

    U Creutzig

  6. University Hospital, Medical Clinic and Policlinic I, University of Technics, Dresden, Germany

    C Thiede

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Damm, F., Thol, F., Hollink, I. et al. Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML–BFM and DCOG study groups. Leukemia 25, 1704–1710 (2011). https://doi.org/10.1038/leu.2011.142

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