title: IDH1 and IDH2 mutations in pediatric acute leukemia.
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.
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Andersson
authors.forename: D W
authors.initials: DW
authors.lastname: Miller
authors.forename: J A
authors.initials: JA
authors.lastname: Lynch
authors.forename: A S
authors.initials: AS
authors.lastname: Lemoff
authors.forename: Z
authors.initials: Z
authors.lastname: Cai
authors.forename: S B
authors.initials: SB
authors.lastname: Pounds
authors.forename: I
authors.initials: I
authors.lastname: Radtke
authors.forename: B
authors.initials: B
authors.lastname: Yan
authors.forename: J D
authors.initials: JD
authors.lastname: Schuetz
authors.forename: J E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: R C
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: S C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: C G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: S A
authors.initials: SA
authors.lastname: Shurtleff
authors.forename: B A
authors.initials: BA
authors.lastname: Schulman
authors.forename: J R
authors.initials: JR
authors.lastname: Downing
mesh_terms: D001483:Base Sequence; D002648:Child; D002852:Chromatography, Ion Exchange; D017931:DNA Primers; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics*; D053719:Tandem Mass Spectrometry
chemical_list: D017931:DNA Primers; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human