Acute lymphoblastic leukemia
(ALL) represents the most frequent type of cancer in children and young adults. Despite a good general prognosis and increased survival rates over the past decades, outcomes have not improved for the approximately 25 percent of patients who relapse after initially successful treatment. More than 60 percent of patients who experience ALL bone marrow relapse will die from their disease.
Now, a team led by City of Hope’s Markus Müschen
, M.D., Ph.D., founding chair of the Department of Systems Biology and the Norman and Sadie Lee Foundation Endowed Professor in Pediatrics, thinks that sugar uptake and energy supply may play a key role in the relapse of ALL.
A paper published in the Feb. 13 issue of the journal Nature outlines their findings, which point to increased glucose as the driver of the energy needed for specific cells to transform into malignant cancer cells. ALL typically arises from B cells, which are known for producing antibodies in the human immune system. B cells can also transform into childhood leukemia when something goes wrong in their development.
By taking a closer look at how B cells are regulated, Müschen and colleagues found that factors that determine B cell identity can also restrict glucose — or sugar — and energy supply. 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 Müschen, who recently joined Beckman Research Institute
of City of Hope.
“The low energy levels in normal B cells are simply too low to allow transformation to cancer and leukemia,” said Lai Chan, Ph.D., the study’s first author and assistant professor in the Department of Systems Biology.
The team also found that deletion of genes that encode B cell-determining factors occur in almost all cases of childhood leukemia. Conversely, they saw that the addition of large amounts of sugar can make B cells susceptible to malignant transformation by giving them the energy needed for tumor formation.
Müschen says these results back up a previous finding that obese children with high blood sugar levels are much more likely to develop drug-resistant leukemia and experience relapse than children who are not overweight. The findings also indicate that dieting could be an important consideration for children who have survived leukemia.
Avoiding obesity and excessive energy supply, or sugar, may help to decrease the risk of leukemia relapse,” he said.
To test that theory, Müschen plans to perform experiments in animal models to evaluate the efficacy of dietary restriction on patient-derived childhood leukemia cells.
He also plans to assess the activity of drugs that reduce the ability of leukemia cells to take up glucose and energy supply.
Since future relapse patients are indistinguishable 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 an aggressive regimen and will suffer late effects from unnecessary toxicity, said Müschen.
“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 said.