Results published in Nature also include a proposal for a new treatment concept based on new findings
— An international team of researchers led by City of Hope’s Markus Müschen
, M.D., Ph.D., 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, according to the paper titled, “Metabolic gatekeeper function of B-lymphoid transcription factors,” published today in Nature
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 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, Müschen and colleagues at City of Hope 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 Müschen, who recently joined the 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.”
In agreement with this finding, 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, 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, Müschen 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, Ph.D., the study’s first author and assistant professor in the Department of Systems Biology
To test that theory, Müschen 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,” Müschen 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 added.
The work described in the Nature paper was supported by the National Institutes of Health and the National Cancer Institute through an Outstanding Investigator Award R35CA197628 and grants R01CA137060, R01CA157644 and R01CA172558.
About City of Hope
City of Hope is an independent research and treatment center for cancer, diabetes and other life-threatening diseases. Designated as one of only 47 comprehensive cancer centers, the highest recognition bestowed by the National Cancer Institute, City of Hope is also a founding member of the National Comprehensive Cancer Network, with research and treatment protocols that advance care throughout the world. City of Hope is located in Duarte, California, just northeast of Los Angeles, with community clinics
throughout Southern California. It is ranked as one of "America's Best Hospitals" in cancer by U.S. News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation
and numerous breakthrough cancer drugs
based on technology developed at the institution. For more information about City of Hope, follow us on Facebook
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