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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
IDH1 and IDH2 mutations in pediatric acute leukemia
A K Andersson1, D W Miller, J A Lynch
1Department of Pathology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Leukemia
|June 8, 2011
Summary
Isocitrate dehydrogenase (IDH) mutations are rare in childhood acute lymphoid leukemia but occur in 3.5% of acute myeloid leukemia cases, particularly those with normal karyotypes. These mutations lead to the production of R(-)-2-hydroxyglutarate (2-HG), a potential oncometabolite.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Isocitrate dehydrogenase (IDH) mutations are implicated in various cancers.
- The role of IDH1 and IDH2 mutations in pediatric leukemias is not well-defined.
Purpose of the Study:
- To determine the frequency of IDH1 and IDH2 mutations in pediatric acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL).
- To characterize the functional consequences of identified mutations and their potential cooperation with other genetic alterations.
Main Methods:
- Sanger sequencing of IDH1 and IDH2 genes in diagnostic samples from 515 pediatric leukemia patients (227 AML, 288 ALL).
- Structural modeling to predict the impact of mutations on enzyme function.
- Biochemical assays using recombinant proteins to assess enzymatic activity.
- Measurement of 2-hydroxyglutarate (2-HG) levels in patient samples.
Main Results:
- Somatic IDH1/IDH2 mutations were rare in ALL (1/288) but present in 3.5% of AML cases (8/227).
- Mutations were more frequent in AML with normal karyotype (9.8%).
- IDH1 mutations affected codon 132, while IDH2 mutations altered codon 140, leading to neomorphic production of 2-HG.
- Elevated 2-HG levels were confirmed in AML patients with IDH1/IDH2 mutations.
- Co-occurrence of IDH2 mutations and FLT3-activating mutations was observed in 3/5 AML cases.
Conclusions:
- IDH1/IDH2 mutations are uncommon in pediatric ALL but represent a significant subset of AML, particularly those with normal karyotypes.
- These mutations result in the production of the oncometabolite 2-HG.
- The frequent co-occurrence of IDH2 and FLT3 mutations suggests potential cooperative roles in AML pathogenesis.
