Aims: Identification of selective metabolic dependencies in cancer cells offers significant promise for the development of new treatment strategies. Heme is an essential metabolite that plays diverse biological functions, including as a catalytic cofactor in hemoproteins and a regulator of signalling and transcription. The aim of this study was to assess the therapeutic potential of targeting heme biosynthesis in acute myeloid leukemia (AML), a poor prognostic malignancy with unmet need.
Methods: We analysed expression of pathway components and quantified heme levels in mouse models, human AML cell lines and patient samples. We tested the impact of modulating heme synthesis on the epigenome, transcriptome and metabolome of leukemic cells. Finally, we employed pooled CRISPR screening to uncover mechanisms of heme starvation-induced cell death and metabolic pathways that are synthetic lethal with heme biosynthesis.
Results: Through integrated analyses of mouse models, human cell lines and primary patient samples, we identify de novo heme biosynthesis as a selective dependency in acute myeloid leukaemia (AML). The dependency is underpinned by a propensity of AML cells, and especially leukaemic stem cells (LSCs), to downregulate heme biosynthesis enzymes (HBEs) which promotes their self-renewal. Inhibition of HBEs causes collapse of mitochondrial Complex IV (CIV) and dysregulates the copper-chaperone system inducing cuproptosis, a form of programmed cell death brought about by the oligomerisation of lipoylated proteins by copper. Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies.
Conclusions: Altogether, our work uncovers a heme rheostat that controls gene expression and drug sensitivity in AML and implicates heme starvation as a novel cuproptosis trigger.