High-risk MDS stem cells may have a dangerous weakness hidden inside their own metabolism: an “energy addiction” that researchers may be able to exploit to selectively attack the cells driving the cancer.
Cancer stem cells can survive treatments that kill many of the other cells around them, allowing disease to persist or return. Now, researchers have identified a possible metabolic weak point in the stem cells behind high-risk myelodysplastic syndromes (MDS), an aggressive group of blood cancers that can progress to acute myeloid leukemia.
The weakness centers on nicotinamide adenine dinucleotide (NAD), a molecule cells need to generate energy and support other essential functions. Scientists at the University of Colorado Anschutz Cancer Center found that high-risk MDS stem cells consume this resource differently from healthy blood-forming stem cells and appear unusually dependent on the cellular machinery that replenishes it.
That dependence could offer researchers something cancer therapies often struggle to find: a biological difference that can be attacked in malignant cells while leaving healthy stem cells better able to cope.
Why High-Risk MDS Is Hard to Treat
“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.”
The findings were published in Blood Cancer Discovery.
MDS begins in the bone marrow, where blood-forming stem cells normally generate red blood cells, white blood cells, and platelets. In the disease, mutated stem cells produce abnormal blood cells that cannot perform those jobs properly.
The consequences can include severe anemia, recurrent infections, bleeding problems, and a need for repeated blood transfusions. In higher-risk cases, the disease can evolve into acute myeloid leukemia (AML).
Why Better MDS Targets Matter
MDS is primarily a disease of older adults, with roughly 10,000-20,000 new diagnoses estimated in the United States each year. National Cancer Institute data place the annual age-adjusted incidence at about 4.4 to 4.6 cases per 100,000 people.
Treatment can include supportive care, drugs such as azacitidine or decitabine, chemotherapy, and stem cell transplantation. An allogeneic stem cell transplant remains the only treatment with established curative potential, but its risks can limit its use, particularly in the older population most commonly affected by MDS.
That makes finding vulnerabilities specific to the cells sustaining the disease especially important.
The Colorado team focused on how MDS stem cells obtain and use energy. Their experiments revealed a striking dependence on the NAD salvage pathway, a recycling system that cells use to restore their supply of NAD.
NAMPT Exposes an MDS Energy Weakness
At the center of that pathway is an enzyme called nicotinamide phosphoribosyltransferase (NAMPT).
When researchers interfered with NAMPT, NAD levels fell. Healthy blood-forming stem cells were comparatively flexible and could adapt by relying more heavily on other metabolic routes. The MDS stem cells could not adjust as effectively.
“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.”
The researchers describe this metabolic dependence as an “energy addiction.” In effect, the malignant stem cells appear to have organized their metabolism around a resource they cannot easily do without.
Targeting Cancer Stem Cells More Precisely
Blocking NAMPT deprived them of that resource, creating an energy crisis that preferentially weakened the cancer stem cells.
That distinction matters because simply finding something cancer cells need is not enough. Healthy cells often need the same molecules and pathways. A useful therapeutic target must ideally expose a difference in how dependent cancer cells are on a particular process.
The team tested the approach using patient-derived MDS cells and animal models. In both settings, disrupting NAD metabolism reduced the stem cells responsible for sustaining the disease.
The results remain preclinical, so they do not yet show that blocking NAMPT will be safe or effective in people with MDS.
What Comes Next for NAMPT Therapy
Still, NAMPT is drawing broader interest as a cancer target. Other recent laboratory studies have also explored whether tumors with unusually high NAD demands can be made vulnerable by interfering with the same salvage pathway, suggesting that abnormal NAD metabolism may represent a wider weakness across some cancers.
For MDS, the next step is to evaluate drugs that target NAMPT in clinical studies involving 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.”
Reference: “The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells” by Sweta B. Patel, Daniel R. Moskop, Steven Moreira, Stephanie Gipson, Colin C. Anderson, Alexandra Crook, Maxwell McCabe, Daniel Stephenson, Hannah E. Terry, Andrew Kent, Tracy N. Young, Anna E. Krug, Connon I. Thomas, Caitlin Price, Monica Ransom, Regan Miller, Ana Vujovic, Mohammad Minhajuddin, Mark J. Althoff, The CUIJBP Consortium, Anthony J. Saviola, Brett M. Stevens, Robert S. Welner, Ekaterina L. Andrianova, Andrei V. Gudkov, Anza Darehshouri, Julie A. Reisz, Travis Nemkov, Angelo D’Alessandro, Austin E. Gillen, Daniel A. Pollyea, Craig T. Jordan and Eric M. Pietras, 21 July 2026, Blood Cancer Discovery.
DOI: 10.1158/2643-3230.BCD-25-0498
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