Data from The Nicotinamide Salvage Pathway Is a Metabolic Vulnerability of High-Risk MDS Stem Cells
Year: 2026
Type: other
Abstract: High-risk myelodysplastic syndrome (HR-MDS) is a malignant clonal disorder originating in hematopoietic stem and progenitor cells (HSPC). The current standard of care for patients with HR-MDS has a poor response, thus necessitating exploration of the vulnerabilities of HR-MDS HSPCs for better clinical outcomes. We demonstrate that compared with healthy HSPCs, HR-MDS HSPCs have significant upregulation of metabolic proteins leading to increased oxygen consumption, suggesting an increased metabolic rate. Corroboratively, compared with healthy HSPCs, HR-MDS HSPCs have an increased abundance of NADH dehydrogenases, which are crucial for energy production. Therefore, we investigated whether HR-MDS HSPCs are functionally reliant on nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting enzyme in the nicotinamide salvage pathway of NAD anabolism. NAMPT inhibition reduced the oxygen-consuming capacity of HR-MDS HSPCs compared with healthy controls. Importantly, NAMPT inhibition significantly impaired function, increased cell death, and reduced disease burden specifically of HR-MDS HSPCs. Collectively, our data suggest that NAMPT is a promising therapeutic target to eradicate HR-MDS HSPCs. Significance: HR-MDS remains a clinically challenging blood disorder, posing a dire need to identify therapeutic targets that improve clinical outcomes. We show that the nicotinamide salvage pathway is a promising target to eliminate HR-MDS HSPCs, the source of the disease.
Authors: 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, 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, Eric M. Pietras
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W7207746667
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