A Hidden Weakness in Blood Cancer Stem Cells: Their Dependence on NAD

Cancer cells are famously greedy, but a new study suggests that some of them are not just hungry, they are dependent. Researchers at the University of Colorado Anschutz Cancer Center have found that the stem cells behind a serious blood cancer rely on one particular energy-related molecule far more than healthy blood-forming cells do. The team calls it an “energy addiction,” and it may be a weakness worth exploiting.

What is high-risk MDS?

Myelodysplastic syndromes (MDS) are cancers of the bone marrow, where blood cells are made. In MDS, the marrow struggles to produce healthy red cells, white cells and platelets. Patients can develop severe anemia, suffer frequent infections and need repeated blood transfusions. In its high-risk form, the disease can progress to acute myeloid leukemia (AML), an aggressive cancer that remains hard to treat.

MDS mostly affects older adults, with an estimated 10,000 to 20,000 new diagnoses each year in the United States.

Why target the stem cells?

Blood production starts with stem cells. In high-risk MDS, mutated stem cells lose the ability to generate normal, functional blood cells and instead produce abnormal ones. Because these stem cells keep the disease going, treatments that hit them precisely, while sparing their healthy counterparts, are a major goal of cancer research.

So the team asked a simple question: how do MDS stem cells differ biologically from normal ones?

The NAD connection

The answer turned out to lie in metabolism. The diseased stem cells leaned heavily on nicotinamide adenine dinucleotide, or NAD, a molecule that is essential to how cells produce and manage energy. Specifically, they depended on the NAD salvage pathway, a recycling system that keeps NAD supplies topped up. One enzyme in that pathway, NAMPT (nicotinamide phosphoribosyltransferase), stood out as a potential drug target.

When the researchers blocked NAMPT, NAD levels dropped and the cancer stem cells hit an energy crisis. Healthy blood-forming stem cells coped better, apparently because they can switch to other ways of producing and managing energy. The MDS stem cells showed much less of that flexibility.

"These cells actually use energy in different ways than normal stem cells do."

Eric M. Pietras, PhD, co-lead author, University of Colorado Anschutz

What the experiments showed

The findings came from experiments with patient-derived MDS cells and animal models. In both, interfering with NAD metabolism reduced the number of disease-driving stem cells. That selectivity is the exciting part: a therapy that exploits a difference between cancer cells and healthy cells has the potential to be more effective and gentler on the patient.

What comes next

It is important to keep expectations realistic. This is laboratory and preclinical work, not a new treatment. The researchers now plan to investigate drugs that target NAMPT in clinical studies involving people with MDS and related blood cancers, the step that will show whether this metabolic weak spot can be turned into a safe and effective therapy.

The study was led by Eric M. Pietras and Craig T. Jordan as co-lead authors, with laboratory work led by Sweta B. Patel, and was supported by the National Institutes of Health, the Edward P. Evans Foundation, Blood Cancer United and other partners.

Sources

·         Original press release: University of Colorado Anschutz researchers identify an “energy addiction” in high-risk blood cancer stem cells (CU Anschutz Medical Campus)

·         Original paper: Patel S.B. et al., The Nicotinamide Salvage Pathway Is a Metabolic Vulnerability of High-Risk MDS Stem Cells. Blood Cancer Discovery, 2026; 7(5):796. DOI: 10.1158/2643-3230.BCD-25-0498 

Source: A Hidden Weakness in Blood Cancer Stem Cells: Their Dependence on NAD