Advanced

IDH1 and IDH2 mutations in pediatric acute leukemia

Andersson, A K LU ; Miller, D W; Lynch, J A; Lemoff, A S; Cai, Z; Pounds, S B; Radtke, I; Yan, B; Schuetz, J D and Rubnitz, J E, et al. (2011) In Leukemia 25(10). p.1570-1577
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)... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
publishing date
type
Contribution to journal
publication status
published
subject
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
in
Leukemia
volume
25
issue
10
pages
8 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:80054035931
ISSN
1476-5551
DOI
10.1038/leu.2011.133
language
English
LU publication?
no
id
0261d57d-9e36-4946-b69f-c4d360a8224c
date added to LUP
2019-06-19 14:10:47
date last changed
2019-10-13 05:03:58
@article{0261d57d-9e36-4946-b69f-c4d360a8224c,
  abstract     = {<p>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.</p>},
  author       = {Andersson, A K and Miller, D W and Lynch, J A and Lemoff, A S and Cai, Z and Pounds, S B and Radtke, I and Yan, B and Schuetz, J D and Rubnitz, J E and Ribeiro, R C and Raimondi, S C and Zhang, J and Mullighan, C G and Shurtleff, S A and Schulman, B A and Downing, J R},
  issn         = {1476-5551},
  keyword      = {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},
  language     = {eng},
  number       = {10},
  pages        = {1570--1577},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {IDH1 and IDH2 mutations in pediatric acute leukemia},
  url          = {http://dx.doi.org/10.1038/leu.2011.133},
  volume       = {25},
  year         = {2011},
}