IDH1 and IDH2 mutations in pediatric acute leukemia

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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
External organisations
  • St Jude Children´s Research Hospital, Memphis
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics

Keywords

  • Base Sequence, Child, Chromatography, Ion Exchange, DNA Primers, Humans, In Situ Hybridization, Fluorescence, Isocitrate Dehydrogenase/genetics, Leukemia, Myeloid, Acute/enzymology, Mutagenesis, Site-Directed, Mutation, Polymerase Chain Reaction, Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology, Tandem Mass Spectrometry
Original languageEnglish
Pages (from-to)1570-1577
Number of pages8
JournalLeukemia
Volume25
Issue number10
Publication statusPublished - 2011 Oct
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes