Researchers at the University of Colorado Anschutz Cancer Center have identified a previously unknown metabolic weakness in the stem cells that drive high-risk myelodysplastic syndromes (MDS), a discovery that could lead to more targeted treatments for this aggressive blood cancer.

Published in Blood Cancer Discovery, the study found that high-risk MDS stem cells are unusually dependent on nicotinamide adenine dinucleotide (NAD), a molecule essential for cellular energy production. By disrupting the pathway that maintains NAD levels, researchers selectively targeted disease-driving stem cells while healthy blood-forming stem cells were better able to adapt.

What we found is that these cells actually use energy in different ways than normal stem cells do. They were relying on a specific set of proteins and processes that created a vulnerability we could potentially target."

Eric M. Pietras, PhD, associate professor, Division of Hematology, University of Colorado Anschutz, co-lead author of the study

What is high-risk myelodysplastic syndrome (MDS)?

Myelodysplastic syndromes are blood cancers in which the bone marrow fails to produce healthy blood cells. Patients may develop severe anemia, frequent infections, and require ongoing blood transfusions. High-risk MDS can progress to acute myeloid leukemia (AML), an aggressive leukemia that remains difficult to treat.

The disease primarily affects older adults. Each year, an estimated 10,000-20,000 people in the United States are diagnosed with MDS.

What did researchers discover?

Blood cancers, like healthy blood production, are driven by stem cells. In high-risk MDS, abnormal stem cells that have acquired genetic mutations fail to produce the normal blood cells needed for carrying oxygen, clotting wounds, and fighting infection. Instead, they only produce diseased blood cells unable to carry out these functions. Researchers wanted to determine what makes these cancer stem cells different from healthy ones.

The team found that MDS stem cells rely heavily on the NAD salvage pathway, a cellular recycling system that maintains NAD levels. A key enzyme in this pathway, nicotinamide phosphoribosyltransferase (NAMPT), emerged as a promising therapeutic target.

"These cells had developed a much greater need for this resource," Pietras said. "They appear to use NAD at a much higher rate than normal cells, which creates a vulnerability that we can exploit with new types of drugs."

Researchers describe this dependence as an "energy addiction." Unlike healthy blood-forming stem cells, MDS stem cells could not easily switch to alternative energy pathways. Blocking NAMPT reduced NAD levels, triggering an energy crisis that selectively weakened the cancer stem cells.

What comes next?

Using patient-derived MDS cells and animal models, the researchers showed that targeting NAD metabolism reduced disease-driving stem cells. The next step is evaluating NAMPT-targeting drugs in clinical studies for patients with MDS and related blood cancers.

"Our goal is to identify approaches that make these complex diseases more treatable by finding the differences between cancer cells and normal cells," Pietras said. "If we can understand those differences, we can begin to develop therapies that are more precise and more effective for patients."

Dr. Pietras and Dr. Craig T. Jordan are both co-lead authors of the study. The laboratory studies for the project were led by Sweta B. Patel, PhD, and included collaborations with researchers at the University of Colorado Anschutz, including Angelo D'Alessadro, PhD and Julie Reisz Haines, PhD, with additional collaborators from multiple institutions. The research was supported by the National Institutes of Health, the Edward P. Evans Foundation, Blood Cancer United, and additional partners committed to advancing blood cancer research.

Source:

Journal reference:

Patel, S. B., et al. (2026). The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells. Blood Cancer Discovery. DOI: 10.1158/2643-3230.bcd-25-0498. https://aacrjournals.org/bloodcancerdiscov/article-abstract/doi/10.1158/2643-3230.BCD-25-0498/786935/The-Nicotinamide-Salvage-Pathway-is-a-Metabolic?redirectedFrom=fulltext