Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia [RNA-Seq DIN]

The ubiquitous metabolite heme has diverse enzymatic and signaling functions in most mammalian cells. 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 leukemia (AML). The dependency is underpinned by a propensity of AML cells, and especially leukemic 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 oligomerization 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. Altogether, our work uncovers a heme rheostat that controls gene expression and drug sensitivity in AML and implicates HBE inhibition as a novel cuproptosis trigger. Overall design: The DIN model was generated by co-transducing fetal liver cells with MSCV-TRI-DNMT3AR882H-dsRed (TRI-DNMT3AR882H), MSCV-GFP-IDH2R140Q (MIG-IDH2R140Q) and MSCV-NRASG12D-TTA (MIT- NRASG12D) into sub-lethally irradiated (5.5Gy whole body irradiation delivered by an X-RAD 320 (Precision) female Ptprca recipients. Cryopreserved cells from moribund mice were transplanted into Ptprca recipients and mice were given either normal or doxycyline chow and water for 5 or 14 days. Doxycyline de-induces the expression of DNMT3AR882H. cKit+/Cd11b- DIN progenitor cells from the bone marrow and spleens of mice were isolated by FACS and subjected to RNA sequencing.