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.

Mutation Analysis of Isocitrate Dehydrogenase in Acute Lymphoblastic Leukemia

“…Subsequently, the mutation was also detected in myeloproliferative neoplasm (Pardanani et al, 2010;Tefferi et al, 2010), myelodysplastic syndrome (Kosmider et al, 2010), and non-Hodgkin lymphoma (Zou et al, 2010). Only three IDH-mutated cases were so far identified in ALL (Kang et al, 2009;Abbas et al, 2010;Andersson et al, 2011). Our observation confirmed the occurrence of IDH1 mutation in ALL.…”

“…Interestingly, the pediatric IDH1-mutated case reported by Andersson et al (2011) also had a normal karyotype and aberrant myeloid antigen expression of CD13 and CD33. The expression of the myeloid antigens in the IDH1 mutation carriers suggested that the leukemia clone of IDH1-mutated ALL may come from an early stage of hematopoiesis and IDH1 mutation may be involved in myeloid differentiation.…”

“…The most popular method is direct sequencing (Abbas et al, 2010;Andersson et al, 2011). In addition, single-strand conformation polymorphism-based assays (Kang et al, 2009;Zou et al, 2010) and real-time PCR with post-PCR fluorescence melting curve analysis assays (Lin et al, 2011;Noordermeer et al, 2011) were also used.…”

“…Kang et al (2009) reported one B-acute lymphoblastic leukemia (B-ALL) case with an IDH1 R132C mutation (1/60; 1.7%). Another single IDH1 mutation, also R132C, was detected in an analysis of 288 pediatric ALL samples by Andersson et al (2011). Abbas et al (2010) reported an ALL case with an IDH2 R140Q mutation (1/96; 1.0%).…”

Cancer-associated Isocitrate Dehydrogenase Mutations Inactivate NADPH-dependent Reductive Carboxylation

“…Interest in IDH biochemistry increased when mutations in one of the two homodimeric IDHs were associated with several subtypes of cancer, including gliomas and leukemias (13)(14)(15)(16). The IDH forward reaction, isocitrate decarboxylation, is inactivated by the common cancer-associated mutations that occur at Arg-132 of IDH1 or the analogous Arg-172 of IDH2 (17)(18)(19)(20)(21).…”