Results published in Nature also include a proposal for a new treatment
concept based on new findings
DUARTE, Calif.–(BUSINESS WIRE)–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 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
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 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,
breakthrough cancer drugs based on technology developed at the
institution. For more information about City
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