Death-defying mechanism drives premature aging in blood stem cells after transplant

For some survivors of childhood cancer, lifesaving treatment can come with a long biological aftershock. Chemotherapy and bone marrow transplantation place intense stress on blood-forming stem cells, and over time, those cells can begin to behave as though they have aged prematurely. Aged stem cells have a reduced ability to create blood cells that carry oxygen and fight infections, and they are more prone to developing into cancerous blood cells than their younger counterparts. Prematurely aged stem cells expose survivors to disease risks associated with far older individuals.

Masayuki Yamashita, MD, PhD, Department of Hematology, has spent much of his career investigating leukemia and the long-term impact of treatment. From his work as a physician in Japan to his current research at St. Jude, he has sought to understand the central blood-forming cells in the body: hematopoietic stem cells. 

“Hematopoietic stem cells can survive many types of stress that no other blood cells can,” Yamashita explained. “Their ability to cope with many kinds of stress makes bone marrow transplantation possible, because they can survive and repopulate the entire blood system, but these stresses still alter their behavior in disadvantageous ways.”

Scientists have observed that after transplantation, blood stem cells often show signs of premature aging. They lose their regenerative abilities and skew their production of blood cells toward certain types at the expense of others. Earlier work traced those effects to mitochondria, the energy-producing organelles, but the exact mechanism was unclear. Recently, Yamashita’s group found that stress can activate MLKL, a protein better known for its role in cell death, but instead of killing blood-forming stem cells, it disrupts their mitochondria. The results were published recently in Nature Communications. 

“We’ve uncovered one of the mechanisms underlying stem cell aging,” said Yamashita, corresponding author of the study. “Surprisingly, it wasn’t linked to gene expression or epigenetic changes, but to alterations in protein-protein interactions of a cell death protein causing mitochondrial dysfunction.” 

Side-stepping cell death in blood stem cells

To study how stress affects these cells, the researchers exposed blood-forming stem cells to inflammatory signals that mimic conditions associated with chemotherapy and transplantation. One molecule stood out: MLKL, which was known by scientists for its role in necroptosis, a form of programmed cell death.

But the team found something unexpected.

“We found that, contrary to expectations, this necroptosis pathway doesn’t always lead to cell death,” said first author Yuta Yamada, MD, PhD, Department of Hematology. In their experiments, stem cells exposed to inflammation were no more likely to die than control cells. Instead, they found that “MLKL molecules preferentially localized in the stem cells’ mitochondria in response to stress, leading to dysfunction.”

Normally, MLKL activation is thought to mark a “point of no return” on the path toward cell death. In these stem cells, however, it appeared to work differently. The scientists found that MLKL was likely making small holes in mitochondria, reducing the electrical gradient required to generate energy. The cells survived, but with their energy-making capacity significantly curtailed. When they mutated MLKL to be unable to make pores in mitochondria, it caused less disruption to mitochondrial function. 

“We are the first to formally demonstrate in primary cells that there is a cell death–independent function of activated MLKL,” Yamashita said. “Our results show that it can alter biological processes in response to stress, which we directly connected to age-related mitochondrial dysfunction in blood stem cells, suggesting the potential for interventions.”

Preventing premature blood stem cell aging

The study did not test a therapy directly. However, it points to a possible strategy for future research: temporarily limiting this pathway during particularly stressful periods, such as chemotherapy, transplantation or gene therapy, to improve blood formation and prevent aging-related diseases.

In mouse experiments, stem cells lacking MLKL repopulated the blood system more effectively after transplantation and retained more regenerative capacity than unaltered cells. Those findings suggest that dampening the pathway could help preserve the body’s ability to make new blood cells.

“We found that stem cells’ blood-forming capabilities are reduced because of the activation of these necroptosis-related proteins,” Yamashita said. “Our study suggests that investigating ways to transiently inhibit necroptosis during stressful events may be a strategy to retain those abilities and prevent premature blood stem cell aging and related diseases.”

Their work also suggested that altering the pathway may reduce posttreatment age-related disease risks. Because aging blood stem cells can be more vulnerable to cancer-related blood disorders, such as myelodysplastic syndrome (MDS), the researchers examined how MLKL affected MDS risk. In their mouse models, removing MLKL reduced susceptibility to disease driven by an MDS-associated oncogene. However, even with such positive initial results, much work needs to be done to find safe and effective interventions.

“Our results suggest that MLKL can promote the development of MDS,” Yamada said. “But in other contexts, it’s known to delay or prevent malignancy. This indicates that we should also be careful about intervening in this pathway, as it has tradeoffs. Inhibiting it might be beneficial for preserving blood formation, but in some contexts, it might also promote disease progression.”

The study provides a foundation for these future investigations, which will need to balance preserving blood formation with the risk of fueling other diseases. However, if scientists can find that equilibrium, it could make a real difference for survivors of childhood cancer.

“After pediatric cancer treatment, patients experience accelerated aging in many cell types, including their blood stem cells,” Yamashita said. “Our findings show that if we can find ways to prevent accelerated stem cell aging that comes from chemotherapy or transplantation, we may be able to protect their quality of life better.”