The Nicotinamide Salvage Pathway is a Metabolic Vulnerability of High-Risk MDS Stem Cells

High-risk myelodysplastic syndrome (HR-MDS) is a malignant clonal disorder originating in hematopoietic stem and progenitor cells (HSPCs). The current standard of care for HR-MDS patients has a poor response, thus necessitating exploration of vulnerabilities of HR-MDS HSPCs for better clinical outcomes. We demonstrate that compared to healthy HSPCs, HR-MDS HSPCs have significant upregulation of metabolic proteins leading to increased oxygen consumption, suggesting an increased metabolic rate. Corroboratively, compared to healthy HSPCs, HR-MDS HSPCs have increased abundance of NADH dehydrogenases, which are crucial for energy production. Therefore, we investigated whether HR-MDS HSPCs are functionally reliant on 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 to healthy. Importantly, NAMPT inhibition significantly impaired function, increased cell death, and reduced disease burden specifically of HR-MDS HSPCs. Collectively, our data suggests that NAMPT is a promising therapeutic target to eradicate HR-MDS HSPCs.