Australian scientists have discovered a fatal weakness in aggressive blood cancer, opening doors to innovative therapies.
Australian researchers have found a new way to kill acute myeloid leukaemia (AML) cells by cutting off their supply of heme, a molecule the cancer needs to survive.
This triggers a newly discovered type of cell death called cuproptosis and could target the stem cells that cause relapse, offering a potential route to more effective treatments for this aggressive blood cancer.
Dr Alexander Lewis, a postdoctoral researcher at Peter Mac, said they had “uncovered a fundamental weakness in AML cells”.
“By blocking AML cells from producing heme, we can switch on cuproptosis, a unique form of cell death, and effectively kill the cells most responsible for causing a cancer relapse.
“This opens the door to new therapies that are potentially more powerful and longer lasting.”
Around 900 Australians are diagnosed with AML each year, and half of patients relapse, with median survival after relapsof of just four to six months.
The study, published in Cell and carried out with WEHI, the Florey Institute, Monash University, Murdoch Children’s Research Institute and the Centre for Cancer Biology, also points to other metabolic pathways that could be targeted to improve future treatments.
Heme is a vital molecule best known for carrying oxygen in red blood cells.
“Cells can salvage heme from the extracellular environment or synthesize heme de novo from succinyl-coenzyme A (CoA) and glycine through a series of 8 enzymatic reactions catalysed by heme biosynthesis enzymes (HBEs) localised in the mitochondria and the cytosol,” the researchers wrote.
“Beyond its function as an oxygen carrier in erythroid cells, heme is required for—and regulates—numerous molecular processes in non-erythroid cells, ranging from mitochondrial energy generation to iron homeostasis, antioxidant defence, kinase signalling, and transcription.
“Heme levels have been shown to modulate cell fate decisions, including differentiation and apoptotic cell death.
“However, despite the potential for altered heme biosynthesis to impact critical features of cancer cells, HBEs have not been extensively investigated as drug targets in cancer.”
The study revealed that heme depletion causes a disruption in copper balance inside AML cells, leading to the breakdown of Complex IV, a key component of the mitochondria.
This collapse initiated a chain reaction that ultimately kills the cancer cells. The researchers noted that AML cells appeared to be particularly vulnerable because they naturally have lower levels of the enzymes that produce heme, making them less able to withstand heme depletion compared with normal blood stem cells.
While promising, the researchers cautioned that much work remained to be done before heme-targeting therapies could reach patients.
“Although these observations suggest that blocking de novo heme synthesis could be a viable therapeutic strategy, we cannot presently exclude the possibility of serious haematological (e.g., haemolysis or thrombotic microangiopathy) or non-haematological toxicities caused by HBE inhibitor use,” they wrote.
“In conclusion, our study identifies heme depletion as a cuproptosis trigger, strengthening the notion that it is a bona fide cell death pathway that may operate in a host of physiological and pathophysiological contexts.
“We also identify HBEs as promising drug targets in AML, with the availability of HBE crystal structures and tool compounds providing a starting point for drug development.”
