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

Abstract

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 is hypomethylating agents; however, the response rate is poor. There is thus a need to explore vulnerabilities of HR-MDS HSPCs for better clinical outcomes. We demonstrate that HR-MDS HSPCs have significant upregulation of metabolic proteins required for glycolysis, citric acid cycle, and oxidative phosphorylation. Consistently, we see increased oxygen consumption rate in HR-MDS HSPCs compared to healthy, suggesting an increased metabolic rate. Corroboratively, compared to healthy HSPCs, HR-MDS HSPCs have increased abundance of mitochondrial complex I proteins, which are NADH dehydrogenases, and 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 significantly decreased NAD(H) in HR-MDS HSPCs. Consequently, NAMPT inhibition reduced the oxygen-consuming capacity of HR-MDS-HSPCs compared to healthy. Importantly, NAMPT inhibition significantly impaired the self-renewal and colony-forming potential, increased cell death and reduced disease burden specifically of HR-MDS HSPCs, compared to healthy controls. Collectively, our data suggest that NAMPT is selectively required for the function and survival of HR-MDS HSPCs representing a promising therapeutic target.