ORIGINAL ARTICLE IDH1 and IDH2 mutations in pediatric acute leukemia

To investigate the frequency of isocitrate dehydrogenase 1(IDH1) and 2 (IDH2) mutations in pediatric acute myeloidleukemia (AML) and acute lymphoid leukemia (ALL), wesequenced these genes in diagnostic samples from 515patients (227 AMLs and 288 ALLs). Somatic IDH1/IDH2 muta-tions were rare in ALL (N¼1), but were more common in AML,occurring in 3.5% (IDH1 N¼3 and IDH2 N¼5), with thefrequency higher in AMLs with a normal karyotype (9.8%). Theidentified IDH1 mutations occurred in codon 132 resulting inreplacement of arginine with either cysteine (N¼3) or histidine(N¼1). By contrast, mutations in IDH2 did not affect thehomologous residue but instead altered codon 140, resultingin replacement of arginine with either glutamine (N¼4) ortryptophan (N¼1). Structural modeling of IDH2 suggested thatcodon 140 mutations disrupt the enzyme’s ability to bind itssubstrate isocitrate. Accordingly, recombinant IDH2 R140Q/Wwere unable to carry out the decarboxylation of isocitrate toa-ketoglutarate (a-KG), but instead gained the neomorphicactivity to reduce a-KG to R(–)-2-hydroxyglutarete (2-HG).Analysis of primary leukemic blasts confirmed high levels of2-HG in AMLs with IDH1/IDH2 mutations. Interestingly, 3/5AMLs with IDH2 mutations had FLT3-activating mutations,raising the possibility that these mutations cooperate inleukemogenesis.Leukemia (2011) 25, 1570–1577; doi:10.1038/leu.2011.133;published online 7 June 2011Keywords: acute myeloid leukemia; pediatric AML; isocitratedehydrogenase; IDH1; IDH2; acute lymphoid leukemia