Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease generated by the acquisition of multiple genetic and epigenetic aberrations which impair the proliferation and differentiation of hematopoietic progenitors and precursors. In the last years, there has been a dramatic improvement in the understanding of the molecular alterations driving cellular signaling and biochemical changes determining the survival advantage, stimulation of proliferation, and impairment of cellular differentiation of leukemic cells. These molecular alterations influence clinical outcomes and provide potential targets for drug development. Among these alterations, an important role is played by two mutant enzymes of the citric acid cycle, isocitrate dehydrogenase (IDH), IDH1 and IDH2, occurring in about 20% of AMLs, which leads to the production of an oncogenic metabolite R-2-hydroxy-glutarate (R-2-HG); this causes a DNA hypermethylation and an inhibition of hematopoietic stem cell differentiation. IDH mutations differentially affect prognosis of AML patients following the location of the mutation and other co-occurring genomic abnormalities. Recently, the development of novel therapies based on the specific targeting of mutant IDH may contribute to new effective treatments of these patients. In this review, we will provide a detailed analysis of the biological, clinical, and therapeutic implications of IDH mutations.

Keywords: gene mutations; isocitrate dehydrogenase; leukemia; targeted therapy.

Figure 1

Domain map structure of isocitrate dehydrogenase (IDH) enzymes. IDH1 and IDH2 are composed of three different domains: Large domain, small domain, and clas domain. IDH2 contains also a 39 amino acid mitochondrial targeting sequence. The amino acids most frequently involved in IDH mutations are shown: arg 132 for IDH1; arg 140 and arg 172 for IDH2.

Figure 2

Enzymatic reactions catalyzed by wild-type and mutant IDH1 and IDH2 enzymes. (A) Normal IDH1 and IDH2 enzymes catalyze a two-step reaction. In the first step, isocitrate is oxidized to an unstable intermediate compound (oxalosuccinate), with concomitant reduction of NADP⁺ to NADPH. In the second step, the oxalosuccinate loses its beta-carbonyl group, which is released as CO₂, giving rise to the formation of α-ketoglutarate (α-KG). The two H⁺ atoms generated during conversion of isocitrate to oxalosuccinate are used for NADP⁺ reduction to NADPH and for conversion of oxalosuccinate to α-KG. (B) Mutant IDH1 and IDH2 enzymes catalyze the reductive conversion of α-KG to (R)-2-hydroxyglutarate (D-2-HG) with concomitant oxidation of NADPH to NADP⁺. α-KG and D-2-HG are very similar from a structural point of view and differ only for the replacement of the ketone group present in α-KG, with the hydroxyl group present in D-2-HG.

Figure 3

Co-mutations observed in IDH1 and IDH2-mutated acute myeloid leukemias (AMLs). The co-mutation pattern for the most frequently mutated genes in AMLs bearing IDH1-R132C, IDH1-R132H, or other IDH1 mutations is shown (data reported in Falini et al. [33]. The co-mutation pattern for the most frequently mutated genes in AMLs bearing IDH2 R140 or ID172 mutations and IDH1+IDH2 mutations is shown (data reported in Meggendorfer et al. [34]).