A diverse range of recurrently mutated genes have been discovered by recent sequencing of the acute myeloid leukaemia (AML) genome which has greatly advanced our understanding of the genomic and epigenomic landscape of this disease. Understanding the functional role that particular genetic lesions have on AML onset and progression is significant for the development of urgently needed novel therapeutic strategies. Our focus is on the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and -2, which are mutated in -20% of AML patients. IDH enzymes catalyse the conversion of isocitrate to alpha ketoglutarate (a-KG), an intermediate in the citric acid cycle and a co-substrate for a-KG dependent dioxygenases that mediate a variety of downstream pathways, including DNA and histone methylation. Upon mutation of catalytically important arginine residues, IDH proteins gain neomorphic activity, whereby a-KG is converted to D-2-hydroxygluterate (D2HG). This oncometabolite is structurally similar to a-KG and can therefore influence the activity of a-KG dependent enzymes. Consequently, this can alter the cell's epigenetic landscape and lead to deregulation of pathways involved in self-renewal and differentiation. Despite the shared neomorphic production of D2HG amongst all IDH-1 and -2 mutants, there is emerging data that indicates there may in fact be significant functional differences between these allelic variants, which could have important therapeutic and prognostic implications in AML. We aim to investigate the similarities and differences between three of the most commonly occurring IDH mutations in AML: IDH1R132H,IDH2R140Q and IDH2R172K.
We will perform differential gene expression analysis on isogenic murine models and human AML cell lines that have been engineered to express a particular IDH mutant variant and integrate these analyses with RNA sequencing data from AML patients. Our cross-model investigation will provide insight into similarities and differences between allelic variants of mutant IDH-1 and -2 with respect to their functional role in AML and response to therapeutic intervention.