Researchers from Australia's Monash University have discovered a key reason why acute myeloid leukemia (AML) is so difficult to treat and therefore cure. The study, led by Associate Professor Ross Dickins from the Australian Centre for Blood Diseases, identifies an important new concept relevant to clinicians involved in the diagnosis and treatment of AML patients (Cell Stem Cell 2019;25(2):258).
AML is characterized by an overproduction of immature white blood cells that fail to mature properly. These leukemia cells crowd the bone marrow, preventing it from making normal blood cells. In turn this causes anemia, infections, and if untreated, death. It remains a significant health problem, with poor outcomes despite chemotherapy and stem cell transplantation.
For decades it has been thought that AML growth is driven by a sub-population of immature cancer cells called leukemia stem cells, which lose their cancerous properties when they mature. Hence there has been growing international interest in developing therapies aimed at forcing immature cancer cells to "grow up."
Using genetically engineered mouse models and human AML cells, Dickins and his team have found that maturation of AML cells is not unidirectional as originally thought, but can instead be reversible.
The team, which also includes researchers from the Walter and Eliza Hall Institute of Medical Research and several international collaborators, found that even mature AML cells can 'turn back the clock' to become immature again.
This plasticity means that even mature AML cells can make a major contribution to future leukemia progression and therapy resistance.
The discovery has significant implications for the way that AML is treated, according to Dickins. "The AML field has traditionally accepted a model where leukemia maturation is a one-way street. By demonstrating reversible leukemia maturation, our study raises doubts around therapeutic strategies that specifically target just leukemia stem cells. It highlights the need to eradicate all tumor cells irrespective of maturation state."
These new findings are important because several new drugs that force leukemia cells to mature have now entered the clinic. The study by Dickins and colleagues will help clinicians re-shape their thinking to find ways to eradicate mature leukemia cells along with their immature counterparts.