Isocitrate dehydrogenase mutations in myeloid malignancies

Abstract

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 (mIDH) 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 mIDH 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 mIDH 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 mIDH 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 mIDH.

Figure 1

IDH mutations in cancer. Mutant IDH1 and IDH2 enzymes result in an increase of the oncometabolite, (R)-2-HG. (R)-2-HG induces a block of cell differentiation by inhibiting the activity of chromatin-modifying histone and DNA demethylases. Inhibition of these epigenetic regulators leads to a ‘hypermethylation signature' that alters gene expression such that cells lose the ability to progress from immature progenitors to a fully differentiated state. (Adapted by permission from Macmillan Publishers Ltd: Prensner and Chinnaiyan, copyright 2011).

Figure 2

Location of IDH2 mutation may influence prognosis in AML. OS in 148 adult patients with IDH2-mutation-positive AML treated in two Medical Research Council (MRC) trials (Republished with permission of the American Society of Hematology; from Green et al.

Figure 3

(R)-2-HG level may serve as a biomarker of prognosis and treatment effects. OS in patients with cytogenetically normal AML with high or normal levels of (R)-2-HG (Adapted from Wang et al.).