IDH1 and IDH2 mutations in pediatric acute leukemia

A. K. Andersson, D. W. Miller, J. A. Lynch, A. S. Lemoff, Z. Cai, S. B. Pounds, I. Radtke, B. Yan, J. D. Schuetz, J. E. Rubnitz, R. C. Ribeiro, S. C. Raimondi, J. Zhang, C. G. Mullighan, S. A. Shurtleff, B. A. Schulman, J. R. Downing

Research output: Contribution to journalArticle

55 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1570-1577
Number of pages8
JournalLeukemia
Volume25
Issue number10
DOIs
StatePublished - Oct 2011

Keywords

  • IDH1
  • IDH2
  • acute lymphoid leukemia
  • acute myeloid leukemia
  • isocitrate dehydrogenase
  • pediatric AML

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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  • Cite this

    Andersson, A. K., Miller, D. W., Lynch, J. A., Lemoff, A. S., Cai, Z., Pounds, S. B., Radtke, I., Yan, B., Schuetz, J. D., Rubnitz, J. E., Ribeiro, R. C., Raimondi, S. C., Zhang, J., Mullighan, C. G., Shurtleff, S. A., Schulman, B. A., & Downing, J. R. (2011). IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia, 25(10), 1570-1577. https://doi.org/10.1038/leu.2011.133