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 (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.

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.