An international team of researchers led by City of Hope's Markus Muschen, MD, PhD, the Norman and Sadie Lee Foundation Endowed Professor in Pediatrics and founding Chair of the Department of Systems Biology, found a connection between drug-resistance in acute lymphoblastic leukemia (ALL) and increased sugar uptake in the ALL cells (Nature 2017; doi:10.1038/nature21076).
ALL represents the most frequent type of cancer in children and young adults. Despite a good general prognosis and increased survival rates over past decades, outcomes have not improved for the approximate 25 percent of patients who relapse after initially successful treatment.
More than 60 percent of patients who experience ALL bone marrow relapse will not survive. Furthermore, future relapse patients are undistinguishable from patients who will respond well to standard chemotherapy. Many of the approximately 110,000 childhood ALL survivors in the U.S. would benefit from milder forms of chemotherapy, yet are treated with aggressive regimen and will suffer late effects from unnecessary toxicity.
To try to get a better understanding of the mechanisms that are at play in ALL, Muschen and colleagues investigated the role of B cells, the cells that produce antibodies in the human immune system. They knew that when their development goes wrong, B cells can give rise to childhood leukemia.
Through their experiments, the team found that factors that determine B cell identity restrict glucose and energy supply and hence, B cells have much lower energy levels than any other cell type.
"While transformation to cancer and childhood leukemia takes large amounts of energy, we discovered that low energy levels in B cells protects from malignant transformation toward leukemia and cancer," said Muschen, who recently joined Beckman Research Institute of City of Hope, and is also a Howard Hughes Medical Institute Faculty Scholar. "The low energy levels in normal B cells are simply too low to allow transformation to leukemia."
The team also found that deletions and mutations of genes that encode B cell-determining factors occur in almost all cases of childhood leukemia. Conversely, the addition of large amounts of sugar can make B cells susceptible to malignant transformation, or tumor formation.
These results back up a previous finding that obese children with high blood sugar levels are much more likely to develop drug-resistant leukemia than children who are not overweight, Muschen added. They also indicate that dieting could be an important consideration for children who have survived leukemia.
"Avoiding obesity and excessive energy supply may help to decrease the risk of leukemia relapse," said Lai Chan, PhD, the study's first author and Assistant Professor in the Department of Systems Biology.
To test that theory, Muschen and his colleagues plan to perform experiments in animal models to evaluate the efficacy of dietary restriction on patient-derived childhood leukemia cells, and to assess the activity of drugs that reduce the ability of leukemia cells to take up glucose and energy supply.
"Based on the outcome of these studies, we plan to introduce dietary restriction and/or glucose-restricting drugs into a clinical trial for children who are at risk to develop leukemia relapse," Muschen said. "We have found drugs that can help restrict energy supply to B cells even when the normal gatekeeper function of B cell-determining factors has already been compromised.
"We found that these drugs strongly work together with existing anti-leukemia drugs, and preclinical safety studies suggest that these drugs can be given to patients without any additional toxicity or adverse side effects," he concluded.