Methionine metabolism as a vulnerability of leukemic stem cells and a therapeutic target in high-risk AML

Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. AML affects all age groups but is most common above the age of 65. It is the most common and most lethal acute leukemia in adults. Even with a variety of new treatments becoming available in recent years, AML remains incurable for most patients, and long-term survival is poor. This is due in large part to the presence of leukemic stem cells, a very small population of cancer cells that have the unique ability to remain dormant, survive treatment, and later reignite the disease.

Research from the Jordan laboratory over the past two decades has shown that leukemic stem cells are distinguished by how they use energy. Their metabolism differs from that of both normal blood cells and the majority of leukemia cells. In particular, they rely heavily on aerobic respiration to sustain their survival and self-renewal. However, attempts to target this metabolic trait have been limited by harmful effects to healthy cells. Therefore, new approaches are needed.

Results from our lab and others suggest that leukemic stem cells may be particularly dependent on the amino acid methionine, which comes from protein in our diet. Methionine is unique among the amino acids because it is used not only to build proteins or generate energy, but also regulates and supports many essential processes inside cells. Changes in the levels of methionine can affect cells’ decisions of whether to live or die, mature, or proliferate. Methionine appears to be particularly important for maintaining the ability of cancer cells to grow and divide in an unregulated manner, and cancer cells require higher amounts of methionine than normal cells, a phenomenon known as “methionine dependence”. The reasons for this dependency and whether it can be exploited therapeutically remain poorly understood.

In this project, we aim to explore whether restricting methionine can selectively impair leukemic stem cells. We will investigate how methionine metabolism supports malignant stem cell survival and explore whether dietary methionine availability can enhance the effects of existing leukemia therapies. By studying this unique metabolic vulnerability, our work has the potential to establish a new and potentially less toxic way to prevent AML treatment resistance and relapse.