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Journal Article
Isocitrate dehydrogenase mutations in myeloid malignancies
2017
Overview
Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in
isocitrate dehydrogenase
(
IDH
) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (also called the ‘citric acid’ or Krebs) cycle. Both IDH2 and IDH1 (localized in the cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Mutant IDH enzymes have neomorphic activity and catalyze reduction of α-KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked differentiation of hematopoietic progenitor cells. The prognostic significance of mutant
IDH
(m
IDH
) is controversial but appears to be influenced by co-mutational status and the specific location of the mutation (
IDH1
-R132,
IDH2
-R140,
IDH2
-R172). Treatments specifically or indirectly targeted to m
IDH
are currently under clinical investigation; these therapies have been generally well tolerated and, when used as single agents, have shown promise for inducing responses in some m
IDH
patients when used as first-line treatment or in relapsed or refractory AML or MDS. Use of mIDH inhibitors in combination with drugs with non-overlapping mechanisms of action is especially promising, as such regimens may address the clonal heterogeneity and the multifactorial pathogenic processes involved in m
IDH
myeloid malignancies. Advances in mutational analysis have made testing more rapid and convenient, and less expensive; such testing should become part of routine diagnostic workup and repeated at relapse to identify patients who may benefit from treatments that target m
IDH
.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Acids
/ Animals
/ Cancer
/ Enzymes
/ Humans
/ Hypoxia
/ Isocitrate Dehydrogenase - genetics
/ Isocitrate Dehydrogenase - metabolism
/ Leukemia
/ Leukemia, Myeloid, Acute - enzymology
/ Leukemia, Myeloid, Acute - epidemiology
/ Leukemia, Myeloid, Acute - genetics
/ Leukemia, Myeloid, Acute - mortality
/ Medicine
/ Mutation
/ Myelodysplastic Syndromes - enzymology
/ Myelodysplastic Syndromes - epidemiology
/ Myelodysplastic Syndromes - genetics
/ Oncology
/ Proteins
/ Review
/ Tumors
