{"doi":"10.64898/2025.12.19.695528","title":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559721,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":777690,"name":"Daniel Moskop","orcid":null,"position":1,"is_corresponding":false},{"id":1461853,"name":"Steven Moriera","orcid":null,"position":2,"is_corresponding":false},{"id":1295249,"name":"Stephanie Gipson","orcid":null,"position":3,"is_corresponding":false},{"id":1461854,"name":"Colin C Anderson","orcid":null,"position":4,"is_corresponding":false},{"id":1461855,"name":"Alexendra Crook","orcid":null,"position":5,"is_corresponding":false},{"id":252044,"name":"Maxwell C. 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