Summary of project PR002804
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002804. The data can be accessed directly via it's Project DOI: 10.21228/M86V71 This work is supported by NIH grant, U2C- DK119886. See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002804 |
| Project DOI: | doi: 10.21228/M86V71 |
| Project Title: | The Nicotinamide Salvage Pathway is a Unique Metabolic target in High-Risk MDS Stem Cells |
| Project Type: | Primary Research Article |
| Project Summary: | High-risk myelodysplastic syndrome (HR-MDS) is an incurable malignant clonal disorder originating in the hematopoietic stem and progenitor cells (HSPC). The current standard of care for HR-MDS patients is hypomethylating agents, like azacitidine; however, the response rate is poor, usually with remission of less than two years. Thus, to improve HR-MDS patient outcomes, an unmet clinical need, it is essential to identify better therapeutic targets by exploring vulnerabilities of HR-MDS HSPCs. We have previously demonstrated that inhibiting protein synthesis is a vulnerability for HR-MDS. Subsequently, we identified that HR-MDS HSPCs have a significant upregulation of metabolic proteins required for glycolysis, TCA cycle and oxidative phosphorylation. Consistently, we see reduced glycolytic and TCA cycle metabolites, but an increased oxygen consumption rate in HR-MDS HSPCs compared to healthy, suggesting an increased metabolic rate. Most of the enriched proteins in HR-MDS either use NAD for energy production, maintain NAD(H) redox balance or use NAD as a cofactor for their function. Therefore, we inhibited NAMPT, the rate-limiting enzyme in the nicotinamide salvage pathway of NAD anabolism, using small molecule inhibitors and genetic approaches. NAMPT inhibition significantly decreased NAD levels, reducing the oxygen consuming capacity of HR-MDS-HSPCs compared to normal. Consequently, to compensate, HR-MDS HSPCs, upon NAMPT inhibition positively enriched metabolic proteins associated with amino acid metabolism, lipid metabolism, and the citric acid cycle increasing carbon flux into the aspartate-malate shuttle and the pentose phosphate pathway, while reducing flux through glycolysis and citric acid cycle. Finally, from a functional perspective, NAMPT significantly impaired self-renewal and colony forming potential of HR-MDS HSPCs compared to normal. Importantly, we observed increased cell death of HR-MDS HSPCs compared to normal in both in vitro cultures and in vivo xenograft studies, indicating NAMPT as a tractable target for therapeutic inhibition in HR- MDS patients. Collectively, our data suggest that NAMPT is uniquely required for the function and survival of HR-MDS HSPCs compared to normal and thus can serve as a promising therapeutic target. |
| Institute: | University of Colorado School of Medicine |
| Department: | Hematology |
| Laboratory: | Jordan / Pietras |
| Last Name: | Anderson |
| First Name: | Colin |
| Address: | 12801 East 17th Avenue, Aurora, CO 80045 |
| Email: | Colin.c.anderson@cuanschutz.edu |
| Phone: | 303-724-3339 |
| Funding Source: | NIH |
| Contributors: | Sweta B. Patel, Daniel Moskop, Steven Moriera, Stephanie Gipson, Colin C. Anderson, Alexendra Crook, Maxwell McCabe, Daniel Stephenson, Hannah E. Terry, Andrew Kent, Tracy Young, Anna Krug, Caitlin Price, Monica Ransom, Regan Miller, Ana Vujovic, Mohammad Minhajuddin, Mark J. Althoff, The CUIJBP Consortium, Anthony Saviola, Brett M. Stevens, Robert S. Welner, Ekaterina L. Andrianova, Andrei V. Gudkov, Travis Nemkov, Angelo D’Alessandro, Austin E. Gillen, Craig T. Jordan*, Eric M. Pietras* |
Summary of all studies in project PR002804
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST004440 | Glutamine and Glucose stable-isotope tracing in NAMPT Inhibition | Homo sapiens | University of Colorado School of Medicine | MS | 2026-01-06 | 1 | 16 | Uploaded data (2.4G)* |
| ST004441 | Global metabolomic differences upon NAMPT inhibition in MDS-L cells | Homo sapiens | University of Colorado School of Medicine | MS | 2026-01-06 | 1 | 16 | Uploaded data (2.2G)* |
