3099 – HEME BIOSYNTHESIS IS A THERAPEUTIC VULNERABILITY IN ACUTE MYELOID LEUKAEMIA

Acute myeloid leukaemia (AML) is an aggressive and deadly blood cancer and is the most common acute leukaemia in adults. Identification of metabolic pathways that are dysregulated in AML offers significant promise for the development of more effective treatments and improved patient outcomes. Heme is a ubiquitous metallo-organic enzymatic co-factor and signalling molecule that is produced de novo in nearly all mammalian cells. Beyond its function as an oxygen carrier in erythroid cells, heme is required for and regulates a plethora of biological processes in non-erythroid cells including energy generation, iron homeostasis, chromatin remodelling and transcription. Through integrated molecular and functional analyses of mouse models, human cell lines and primary patient samples we have identified a heme rheostat that controls multiple fundamental aspects of AML biology. AML cells are characterised by a low heme state, demonstrate increased dependence on heme biosynthesis enzymes (HBEs) in vitro and in vivo, and are sensitive to small molecule HBE inhibitors. By combining genetic and pharmacological modulation of heme levels with RNAseq and ChIPseq we found that heme functionally regulates critical AML gene expression circuits via the heme sensing transcription factors BACH1 and CLOCK. Metabolomic analysis revealed wide-ranging metabolic rewiring in low heme cells and pooled CRISPR screening identified heme reactive metabolic dependencies. Among these, we uncovered an inverse relationship between heme and copper. Acute HBE inhibition in AML cells causes intracellular copper accumulation ultimately triggering programmed cell death via cuproptosis. Altogether, our data identify novel relationships between heme production and other transcriptional and metabolic features of leukaemic cells and identify HBEs as potential drug targets in AML.