Researchers said they discovered a finding that could lead to better treatments for Fanconi anemia (FA), a rare, genetic, pediatric hematologic disorder.
Researchers from West Virginia University said they discovered a finding that could lead to better treatments for Fanconi anemia (FA), a rare, genetic, pediatric hematologic disorder.
Children born with FA, which has an incidence rate of 1 in 136,000 births, have an average lifespan of 20 to 30 years, with most eventually developing leukemia.
FA is characterized by bone marrow (BM) failure, with dysfunctional hematopoietic stem cells (HSCs) and involving at least 22 genes. Evidence suggests that dysregulated energy metabolism is 1 possible way that HSCs fail. FA’s diverse symptoms—from fatigue and shortness of breath to frequent bruising and nosebleeds—may hinge on cellular-level energy production. the researchers said.
Compared with how energy is produced in wild‐type HSCs, FA HSCs are more dependent on oxidative phosphorylation (OXPHOS) relative to glycolysis for energy metabolism and undergo glycolysis‐to‐OXPHOS switch in response to oxidative stress through a p53‐dependent mechanism. But how p53, a protein involved in many cancers, regulates energy metabolism in FA HSCs is not well defined.
Using mouse models, researchers said their study shows that FA HSCs demonstrate significantly lower glycolysis than that in wild-type HSCs, which is linked with an overactivated p53-TP53-induced glycolysis regulator (TIGAR) metabolic axis, a signaling pathway. That overexpressed pathway correlates to the aerobic “rerouting” of the stem cells’ energy production.
In a statement, the university said that a drug that inhibits the overactivation of the p53-TIGAR signal could direct the stem cells’ energy production back to the usual pathway. The study could also help future gene therapy efforts, according to scientist Wei Du, MD, PhD, an assistant professor in the School of Pharmacy and co-leader of the Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program at the WVU Cancer Institute.
“If you know more about diseases of the stem cell—how they regulate energy, and how they regulate differentiation and self-renewal—you probably can improve gene therapy as well,” Du said. “If you can manually balance the energy production of the diseased stem cells then maybe this can be a benefit when you harvest those gene-delivery cells and transplant them into the patient.”
The current standard of care for FA includes bone marrow transplant, but it works less than one-third of the time, Du said. Because of mutations in blood cells as well as other cells, replication of healthy, transplanted normal cells does not work properly, and anemia persists.
Li X, Wu L, Zopp M, Kopelov S, Du W. p53-TP53-Induced glycolysis regulator mediated glycolytic suppression attenuates DNA damage and genomic instability in Fanconi anemia hematopoietic stem cells [published online April 12, 2019]. Stem Cells. doi: 10.1002/stem.3015.