Researchers at the University of Colorado Anschutz Cancer Center have identified a metabolic weakness in the stem cells driving high-risk myelodysplastic syndromes, uncovering an unusual cellular energy dependency that could enable more targeted treatments for the aggressive blood cancer, according to a study published in Blood Cancer Discovery.
NAD Dependence in High-Risk MDS Stem Cells
High-risk myelodysplastic syndrome stem cells rely heavily on nicotinamide adenine dinucleotide, a molecule essential for cellular energy production. According to the study, published in the journal Blood Cancer Discovery, researchers found that disrupting the pathway maintaining NAD levels selectively targeted disease-driving stem cells while healthy blood-forming stem cells adapted more easily. “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.”
Understanding Myelodysplastic Syndromes and Treatment Gaps
Myelodysplastic syndromes are blood cancers where the bone marrow fails to produce healthy blood cells, often causing severe anemia, frequent infections, and a need for ongoing blood transfusions. High-risk MDS frequently progresses to acute myeloid leukemia, an aggressive and difficult-to-treat form of cancer. The disease predominantly impacts older adults, with an estimated 10,000 to 20,000 people diagnosed annually in the United States. According to related findings from PubMed, high-risk MDS originates in hematopoietic stem and progenitor cells, where standard care options have a poor response.
Did you know? High-risk MDS stem cells exhibit significantly increased oxygen consumption and an abundance of NADH dehydrogenases compared to healthy hematopoietic stem and progenitor cells, according to data cited on PubMed.
The Role of the NAD Salvage Pathway and NAMPT
Blood cancers are driven by stem cells that acquire genetic mutations, failing to produce normal cells for oxygen transport, wound clotting, and infection defense. To understand why cancer stem cells behave differently than healthy ones, the research team examined metabolic pathways. They discovered that MDS stem cells rely heavily on the NAD salvage pathway, a cellular recycling system maintaining NAD levels. A key enzyme in this process, nicotinamide phosphoribosyltransferase, serves as the rate-limiting enzyme in NAD anabolism and acts as a promising therapeutic target.
“These cells had developed a much greater need for this resource,” Pietras noted, explaining that abnormal stem cells use NAD at a much higher rate than normal cells. This high consumption creates what researchers describe as an energy addiction. Unlike healthy blood-forming stem cells, MDS stem cells cannot easily switch to alternative energy pathways. Blocking NAMPT reduces NAD levels, triggers an energy crisis, and selectively impairs the function and survival of cancer stem cells.
Next Steps for Clinical Evaluation
Using patient-derived MDS cells and animal models, the research team demonstrated that targeting NAD metabolism successfully reduced disease-driving stem cells and lowered overall disease burden. PubMed data further corroborates that NAMPT inhibition specifically impairs function and increases cell death in high-risk MDS stem and progenitor cells. The next phase of research involves evaluating NAMPT-targeting drugs in clinical studies for patients diagnosed with MDS and related blood cancers. Dr. Pietras co-led the study alongside Dr. Craig T. Patel, PhD. Collaborators included Angelo D’Alessadro, PhD, and Julie Reisz Haines, PhD, alongside researchers from multiple institutions. The work received support from the National Institutes of Health, the Edward P. Evans Foundation, and Blood Cancer United.
Frequently Asked Questions
What is high-risk myelodysplastic syndrome?
High-risk myelodysplastic syndrome is a malignant clonal blood cancer where bone marrow fails to produce healthy blood cells, often leading to severe anemia, infections, and potential progression to acute myeloid leukemia.
How do MDS stem cells differ from healthy stem cells?
MDS stem cells rely heavily on the NAD salvage pathway and consume energy at a much higher rate than normal cells, creating an metabolic vulnerability that researchers can target with NAMPT inhibitors.
What is the next step for this research?
Following successful tests in patient-derived cells and animal models, researchers plan to evaluate NAMPT-targeting drugs in clinical trials for patients with MDS and related blood cancers.