Research reveals new clues to why some leukaemia patients respond better to treatment

Researchers in Adelaide and Singapore have uncovered new clues as to why some people with chronic myeloid leukaemia (CML) respond better to treatment than others, identifying that mitochondrial function in cancer cells could potentially be targeted to improve responses.

Published in HemaSphere, the study led by Dr Ilaria Pagani and Associate Professor David Ross examined mitochondrial DNA mutations in 120 patients with chronic-phase CML, revealing a relationship between mitochondrial genetics, cancer cell metabolism and responses to treatment.

Dr Pagani says that mitochondria, often described as the powerhouses of cells, may play a much greater role in determining treatment success than previously thought.

“We found that mitochondrial DNA mutations aren’t simply incidental findings, they appear to be linked to how well patients respond to frontline treatment,” Dr Pagani said.

“The cells from patients with poorer responses appeared to have fitter, more active mitochondria. This may provide them with the energy and flexibility they need to survive treatment pressure.”

Chronic myeloid leukaemia is typically treated with tyrosine kinase inhibitors (TKIs), such as imatinib, which have transformed survival rates for patients to be close to that of the general population. While most patients respond well to these therapies, some achieve slower or less effective responses, and researchers have long sought to understand why.

The study found that leukaemia cells from poorer responders relied more heavily on mitochondrial energy production, revealing a potential vulnerability that could be targeted therapeutically.

To explore this possibility, researchers treated CML stem and progenitor cells with a mitochondrial inhibitor. In preclinical experiments, the treatment reduced the cells’ ability to grow and survive. When combined with imatinib, the effect was even stronger, almost eliminating colony formation entirely.

"While mitochondrial inhibitors aren’t currently used to treat chronic myeloid leukaemia, our findings show proof-of-concept that disrupting the way these cancer cells generate energy may improve responses to existing TKI therapies,” A/Prof Ross said.

“More broadly, this work provides a new framework for using mitochondrial genetics to identify metabolic vulnerabilities, not only in CML, but potentially in other cancers treated with targeted therapies.”

“By combining genetic and metabolic information, we may eventually be able to identify patients who are less likely to respond well to imatinib and develop more personalised treatment approaches.”

The study brought together complementary expertise and resources from three countries. The team at the University of Glasgow shared experimental protocols that were established at SAHMRI, while researchers in Singapore contributed their expertise and a unique single-cell dataset. Dr Pagani identified the dataset could be examined from a new perspective by screening it for mitochondrial DNA mutations.

“This discovery was only possible because researchers were willing to share their methods, data and expertise,” Dr Pagani said.

“The Glasgow protocols allowed us to study how patient cells produced energy, while the Singapore data allowed us to examine mitochondrial mutations in thousands of individual cells. Bringing these different pieces together gave us a much clearer picture of why some leukaemia cells respond poorly to imatinib.”

The collaboration involved patient samples sourced from Australasian Leukaemia and Lymphoma Group (ALLG) clinical trials, and investigators from SAHMRI, SA Pathology, Adelaide University, Royal Perth Hospital, WEHI, the University of Glasgow, Duke-NUS Medical School and Singapore General Hospital. Major contributors included Professor Tim Hughes, Dr Vaidehi Krishnan, Dr John Ouyang and Professor Tiong Ong in Singapore and Professor Vignir Helgason, alongside collaborators across Australia.