Oral Presentation 38th Lorne Cancer Conference 2026

Cu-Later AML:Inhibition of Heme Biosynthesis Triggers Cuproptosis in Acute Myeloid Leukaemia (131760)

Alexander C Lewis 1 , Emily Gruber 1 , Rheana Franich 1 , Jessica Armstrong 1 , Madison Kelly 1 , Carlos Opazo 2 , Yau Chung Low 3 , Lea Flippe 3 , Kevin Wijanarko 3 , Caitlin Rowe 4 , Celeste Mawal 2 , Alexandra Birrell 1 , Joan So 1 , Srimayee Vaidyanathan 5 , Keziah Ting 1 , Liana N Semcesen 6 , Karena Last 6 , Ching-Seng Ang 6 , Giovanna Pomilio 7 , Fiona C Brown 7 , Andrew H Wei 7 , Jason A Powell 5 , Elizabeth Ng 3 , Ann Frazier 3 , Kate McArthur 4 , Najoua Lalaoui 1 , David Stroud 6 , Kristin K Brown 1 , Ricky Johnstone 1 , Lev Kats 1
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Florey Institute of Neuroscience and Mental Health, Melbourne
  3. Murdoch Children’s Research Institute, Melbourne, VIC, Australia
  4. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
  5. Centre for Cancer Biology, Adelaide, SA, Australia
  6. University of Melbourne, Melbourne, VIC, Australia
  7. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia

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 work1 uncovers a heme rheostat that controls gene expression and drug sensitivity in AML and implicates heme starvation as a novel cuproptosis trigger.

1. Lewis AC#, Gruber E#, Franich R, Armstrong J, Kelly MJ, Opazo CM, Low YC, Flippe L, Wijanarko K, Rowe CL, Mawal CH, Birrell A, So J, Vaidyanathan S, Ting K, Semcesen LN, Last K, Ang C-S, Pomilio G, Brown F, Wei AH, Powell JA, Ng ES, Frazier AE, McArthur K, Lalaoui N, Stroud DA, Brown KK, and Johnstone RW, Kats LM, “Inhibition of Heme Biosynthesis Triggers Cuproptosis in Acute Myeloid Leukaemia”, Cell, Accepted, #Equal first author