The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

Abstract

Of the many genetic alterations that occur in cancer, relatively few have proven to be suitable for the development of targeted therapies. Mutations in isocitrate dehydrogenase (IDH) 1 and -2 increase the capacity of cancer cells to produce a normally scarce metabolite, D-2-hydroxyglutarate (2-HG), by several orders of magnitude. The discovery of the unusual biochemistry of IDH mutations spurred a flurry of activity that revealed 2-HG as an 'oncometabolite' with pleiotropic effects in malignant cells and consequences for anti-tumour immunity. Over the next decade, we learned that 2-HG dysregulates a wide array of molecular pathways, among them a large family of dioxygenases that utilise the closely related metabolite α-ketoglutarate (α-KG) as an essential co-substrate. 2-HG not only contributes to malignant transformation, but some cancer cells become addicted to it and sensitive to inhibitors that block its synthesis. Moreover, high 2-HG levels and loss of wild-type IDH1 or IDH2 activity gives rise to synthetic lethal vulnerabilities. Herein, we review the biology of IDH mutations with a particular focus on acute myeloid leukaemia (AML), an aggressive disease where selective targeting of IDH-mutant cells is showing significant promise.

Keywords: 2-HG; IDH mutation; acute myeloid leukaemia; targeted therapies.

Figure 1.. Pleiotropic effects of 2-HG.

In cancer, IDH-mutant cells reduce the TCA metabolite α-KG to 2-HG which accumulates to supraphysiological levels and dysregulates a multitude of pathways to promote increased self-renewal and differentiation arrest. 2-HG can inhibit α-KG-dependent dioxygenases which are involved in a broad range of cellular functions including epigenetic regulation (histone and DNA demethylation), alkylated DNA repair, epitranscriptomic regulation (m6A demethylation), phospholipid biosynthesis and HIF-1α regulation. 2-HG can also induce large metabolic reprogramming, such as an increased vulnerability to oxidative stress driven in part by the consumption of NADPH for 2-HG production and increased reliance upon glutamine metabolism for glutamate production.