Acute myeloid leukaemia (AML) is a devastating disease and there is an urgent unmet need to develop novel treatment strategies. ~20% of AML patients carry mutations in genes that encode the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and -2. Mutant IDH proteins possess a neomorphic enzymatic activity and produce the onco-metabolite D-2-hydroxyglutarate (2-HG) that modulates numerous pathways implicated in cell fate decisions and cancer. Small molecules that block 2-HG production have recently entered clinical trials, however, a detailed understanding of molecular determinants of therapy response and resistance to inhibition of mutant IDH is still lacking. We have generated a series of clinically relevant murine AML models wherein inducible expression of mutant IDH proteins is a driving oncogenic mechanism. We show that genetic depletion and pharmacological inhibition of mutant IDH in vivo has striking effects, triggering differentiation of leukemic cells and increasing survival of tumour bearing mice by >50%. To uncover the molecular program underlying this oncogene addiction we integrated RNA sequencing and chromatin profiling and identified key downstream pathways including GATA1 that are critical for leukaemia maintenance. Our studies provide important mechanistic insight into the oncogenic properties of mutant IDH proteins in maintaining the transformed state of AML cells.