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Acute Leukemias

IDH1 and IDH2 mutations in pediatric acute leukemia

Leukemia volume 25, pages 1570–1577 (2011)Cite this article

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Abstract

To investigate the frequency of isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in pediatric acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), we sequenced these genes in diagnostic samples from 515 patients (227 AMLs and 288 ALLs). Somatic IDH1/IDH2 mutations were rare in ALL (N=1), but were more common in AML, occurring in 3.5% (IDH1 N=3 and IDH2 N=5), with the frequency higher in AMLs with a normal karyotype (9.8%). The identified IDH1 mutations occurred in codon 132 resulting in replacement of arginine with either cysteine (N=3) or histidine (N=1). By contrast, mutations in IDH2 did not affect the homologous residue but instead altered codon 140, resulting in replacement of arginine with either glutamine (N=4) or tryptophan (N=1). Structural modeling of IDH2 suggested that codon 140 mutations disrupt the enzyme's ability to bind its substrate isocitrate. Accordingly, recombinant IDH2 R140Q/W were unable to carry out the decarboxylation of isocitrate to α-ketoglutarate (α-KG), but instead gained the neomorphic activity to reduce α-KG to R(–)-2-hydroxyglutarete (2-HG). Analysis of primary leukemic blasts confirmed high levels of 2-HG in AMLs with IDH1/IDH2 mutations. Interestingly, 3/5 AMLs with IDH2 mutations had FLT3-activating mutations, raising the possibility that these mutations cooperate in leukemogenesis.

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Acknowledgements

This study was supported by National Institutes of Health Grants P01 CA040046 (JRD) and P30 CA021765 (Cancer Center Support Grant to St Jude Children's Research Hospital), Leukemia and Lymphoma Society Specialized Center of Research grant LLS7015 (JRD), and the American Lebanese Syrian Associated Charities (ALSAC) of St Jude Children's Research Hospital. AA was supported by the Swedish Childhood Cancer Foundation, CGM is a Pew Scholar in the Biomedical Sciences and BAS is an Investigator of the Howard Hughes Medical Institute. We would also like to thank Claire Boltz, Letha Phillips and Michael Gebhardt for technical assistance.

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Authors and Affiliations

  1. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA

    A K Andersson, Z Cai, I Radtke, S C Raimondi, J Zhang, C G Mullighan, S A Shurtleff & J R Downing

  2. Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA

    D W Miller & B A Schulman

  3. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA

    J A Lynch & J D Schuetz

  4. Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN, USA

    A S Lemoff & B Yan

  5. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA

    S B Pounds

  6. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA

    J E Rubnitz & R C Ribeiro

  7. Howard Hughes Medical Institute, St Jude Children's Research Hospital, Memphis, TN, USA

    B A Schulman

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  1. A K Andersson
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Correspondence to J R Downing.

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Andersson, A., Miller, D., Lynch, J. et al. IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia 25, 1570–1577 (2011). https://doi.org/10.1038/leu.2011.133

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