Researchers at the University of Colorado Anschutz Cancer Center have uncovered a metabolic vulnerability in the stem cells responsible for driving high-risk myelodysplastic syndromes (MDS), raising the possibility of treatments designed to attack malignant blood-forming cells while sparing their healthy counterparts. The study, published in Blood Cancer Discovery, identifies the nicotinamide adenine dinucleotide (NAD) salvage pathway as a critical dependency of aggressive MDS stem cells.
MDS is a group of blood cancers in which the bone marrow produces abnormal, ineffective blood cells. Patients can develop severe anemia, recurrent infections and bleeding problems because their bodies cannot generate adequate red cells, white cells or platelets. High-risk forms of the disease may progress to acute myeloid leukemia (AML), a rapidly advancing cancer that remains difficult to control, particularly in the older adults most commonly affected by MDS. An estimated 10,000 to 20,000 people in the United States are diagnosed with the disease each year.
Like many blood cancers, MDS is sustained by a small population of self-renewing stem cells. These cells carry disease-associated mutations and generate the abnormal blood cells that accumulate in the bone marrow. Although they are relatively rare, MDS stem cells are considered a major reason the disease can persist or return after treatment. The Colorado-led team set out to determine whether these malignant stem cells possess biological features that distinguish them from healthy hematopoietic stem cells, which continually replenish the blood throughout a person’s life.
Their investigation focused on NAD, a coenzyme required for several fundamental cellular processes. NAD helps cells extract energy from nutrients, supports mitochondrial function and participates in chemical reactions involved in DNA repair and stress responses. Because NAD is continuously consumed, cells must replenish it through biochemical pathways. One of the most important is the NAD salvage pathway, which recycles vitamin B3-related compounds, including nicotinamide, back into usable NAD.
The researchers found that high-risk MDS stem cells depend unusually heavily on this recycling system. In particular, the cells showed a strong reliance on nicotinamide phosphoribosyltransferase, or NAMPT, an enzyme that catalyzes a rate-limiting step in the salvage pathway. This dependence appeared to reflect the unusually high rate at which malignant stem cells use NAD to maintain their metabolism and survival. Healthy blood-forming stem cells, by contrast, were better able to adjust their metabolism when NAD production through the salvage pathway was disrupted.
“What we found is that these cells actually use energy in different ways than normal stem cells do,” said Eric M. Pietras, PhD, associate professor in the Division of Hematology at the University of Colorado Anschutz and co-lead author of the study. “They were relying on a specific set of proteins and processes that created a vulnerability we could potentially target.”
To test whether this metabolic dependence could be exploited, the team blocked NAMPT activity in patient-derived MDS cells and in animal models of the disease. Inhibition of the enzyme reduced the supply of NAD inside the malignant cells. As NAD levels fell, the MDS stem cells experienced what the researchers describe as an energy crisis: their ability to generate energy, maintain cellular balance and withstand stress deteriorated. The treatment reduced the population of disease-driving stem cells, while normal blood-forming stem cells demonstrated greater resilience.
The findings suggest that MDS stem cells are metabolically “addicted” to NAD salvage. Cancer cells often rewire their metabolism to support rapid growth or survival under hostile conditions, but that adaptation can create a liability. By becoming highly dependent on one biochemical route, the cells may lose the flexibility that allows healthy stem cells to switch between alternative sources of energy. In this case, the malignant cells’ increased demand for NAD appears to make them more sensitive to NAMPT inhibition.
The work does not yet establish a treatment for patients, and NAMPT-targeting drugs will require further testing to determine their safety, dosing and effectiveness in people with MDS or related blood cancers. Nevertheless, the researchers say the results provide a rationale for evaluating these agents in clinical studies, potentially in combination with existing therapies. The broader goal is to identify metabolic differences that can be used to eliminate cancer stem cells without causing the widespread damage associated with conventional treatments.
Craig T. Jordan, PhD, and Pietras served as co-lead authors. Laboratory studies were led by Sweta B. Patel, PhD, with contributions from Angelo D’Alessandro, PhD, Julie Reisz Haines, PhD, and collaborators at the University of Colorado Anschutz and other institutions. The research was supported by the National Institutes of Health, the Edward P. Evans Foundation, Blood Cancer United and additional organizations supporting blood cancer research. The team’s findings offer a detailed view of how malignant stem cells sustain themselves—and suggest that disrupting their metabolic fuel supply could become a new strategy against one of the bone marrow’s most persistent diseases.
Subject of Research: High-risk myelodysplastic syndromes (MDS) and the metabolic dependence of MDS stem cells on the NAD salvage pathway.
Article Title: “The Nicotinamide Salvage Pathway is a Metabolic Vulnerability in Myelodysplastic Syndrome Stem Cells”
Web References: University of Colorado Anschutz Cancer Center: https://medschool.cuanschutz.edu/colorado-cancer-center ; Published study: https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-25-0498/786935/The-Nicotinamide-Salvage-Pathway-is-a-Metabolic
References: Blood Cancer Discovery, DOI: 10.1158/2643-3230.BCD-25-0498.
Keywords: Myelodysplastic syndromes, MDS stem cells, NAD metabolism, nicotinamide salvage pathway, NAMPT, blood cancer, acute myeloid leukemia, cancer metabolism, hematopoietic stem cells, targeted therapy
