MDS is a group of blood cancers in which the bone marrow produces abnormal, ineffective blood cells. Patients can develop severe anemia, recurrent infections and bleeding problems because their bodies cannot generate adequate red cells, white cells or platelets. High-risk forms of the disease may progress to acute myeloid leukemia (AML), a rapidly advancing cancer that remains difficult to control, particularly in the older adults most commonly affected by MDS. An estimated 10,000 to 20,000 people in the United States are diagnosed with the disease each year.

Like many blood cancers, MDS is sustained by a small population of self-renewing stem cells. These cells carry disease-associated mutations and generate the abnormal blood cells that accumulate in the bone marrow. Although they are relatively rare, MDS stem cells are considered a major reason the disease can persist or return after treatment. The Colorado-led team set out to determine whether these malignant stem cells possess biological features that distinguish them from healthy hematopoietic stem cells, which continually replenish the blood throughout a person’s life.

Their investigation focused on NAD, a coenzyme required for several fundamental cellular processes. NAD helps cells extract energy from nutrients, supports mitochondrial function and participates in chemical reactions involved in DNA repair and stress responses. Because NAD is continuously consumed, cells must replenish it through biochemical pathways. One of the most important is the NAD salvage pathway, which recycles vitamin B3-related compounds, including nicotinamide, back into usable NAD.

The researchers found that high-risk MDS stem cells depend unusually heavily on this recycling system. In particular, the cells showed a strong reliance on nicotinamide phosphoribosyltransferase, or NAMPT, an enzyme that catalyzes a rate-limiting step in the salvage pathway. This dependence appeared to reflect the unusually high rate at which malignant stem cells use NAD to maintain their metabolism and survival. Healthy blood-forming stem cells, by contrast, were better able to adjust their metabolism when NAD production through the salvage pathway was disrupted.

“What we found is that these cells actually use energy in different ways than normal stem cells do,” said Eric M. Pietras, PhD, associate professor in the Division of Hematology at the University of Colorado Anschutz and co-lead author of the study. “They were relying on a specific set of proteins and processes that created a vulnerability we could potentially target.”

To test whether this metabolic dependence could be exploited, the team blocked NAMPT activity in patient-derived MDS cells and in animal models of the disease. Inhibition of the enzyme reduced the supply of NAD inside the malignant cells. As NAD levels fell, the MDS stem cells experienced what the researchers describe as an energy crisis: their ability to generate energy, maintain cellular balance and withstand stress deteriorated. The treatment reduced the population of disease-driving stem cells, while normal blood-forming stem cells demonstrated greater resilience.

The findings suggest that MDS stem cells are metabolically “addicted” to NAD salvage. Cancer cells often rewire their metabolism to support rapid growth or survival under hostile conditions, but that adaptation can create a liability. By becoming highly dependent on one biochemical route, the cells may lose the flexibility that allows healthy stem cells to switch between alternative sources of energy. In this case, the malignant cells’ increased demand for NAD appears to make them more sensitive to NAMPT inhibition.

The work does not yet establish a treatment for patients, and NAMPT-targeting drugs will require further testing to determine their safety, dosing and effectiveness in people with MDS or related blood cancers. Nevertheless, the researchers say the results provide a rationale for evaluating these agents in clinical studies, potentially in combination with existing therapies. The broader goal is to identify metabolic differences that can be used to eliminate cancer stem cells without causing the widespread damage associated with conventional treatments.

Craig T. Jordan, PhD, and Pietras served as co-lead authors. Laboratory studies were led by Sweta B. Patel, PhD, with contributions from Angelo D’Alessandro, PhD, Julie Reisz Haines, PhD, and collaborators at the University of Colorado Anschutz and other institutions. The research was supported by the National Institutes of Health, the Edward P. Evans Foundation, Blood Cancer United and additional organizations supporting blood cancer research. The team’s findings offer a detailed view of how malignant stem cells sustain themselves—and suggest that disrupting their metabolic fuel supply could become a new strategy against one of the bone marrow’s most persistent diseases.

Subject of Research: High-risk myelodysplastic syndromes (MDS) and the metabolic dependence of MDS stem cells on the NAD salvage pathway.

Article Title: “The Nicotinamide Salvage Pathway is a Metabolic Vulnerability in Myelodysplastic Syndrome Stem Cells”

Web References: University of Colorado Anschutz Cancer Center: https://medschool.cuanschutz.edu/colorado-cancer-center ; Published study: https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-25-0498/786935/The-Nicotinamide-Salvage-Pathway-is-a-Metabolic

References: Blood Cancer Discovery, DOI: 10.1158/2643-3230.BCD-25-0498.

Keywords: Myelodysplastic syndromes, MDS stem cells, NAD metabolism, nicotinamide salvage pathway, NAMPT, blood cancer, acute myeloid leukemia, cancer metabolism, hematopoietic stem cells, targeted therapy

The investigation began with comprehensive analyses of multiple gene expression datasets, revealing that SLC6A6 is ubiquitously expressed across AML cases independent of cytogenetic abnormalities or French-American-British (FAB) classification subtypes. Notably, higher expression levels of this transporter were correlated with resistance to venetoclax, a BCL-2 inhibitor that has revolutionized AML treatment but often encounters resistance in clinical settings. This finding indicates that SLC6A6 might contribute to the metabolic adaptations that enable leukemic cells to evade therapeutic pressure.

Further dissection of AML cellular heterogeneity demonstrated that SLC6A6 expression is particularly enriched in reactive oxygen species (ROS)-low leukemia stem cells within monocytic AML subtypes. These ROS-low LSCs are clinically associated with heightened resistance to venetoclax, suggesting that the taurine transporter supports a metabolic state conducive to cell survival under oxidative stress conditions. The study also revealed that leukemic cells bearing oncogenic RAS mutations exhibit amplified SLC6A6 expression relative to wild-type cells, an association aligned with previous data linking RAS pathway activation to therapeutic resistance.

Importantly, SLC6A6 expression was found to be increased in relapsed AML cases originating from stem or progenitor cell populations, underscoring the transporter’s likely involvement in disease persistence and relapse. Collectively, these multi-faceted insights emphasize SLC6A6 as a crucial player across the AML spectrum, particularly in subsets demonstrating refractoriness to current frontline treatments.

To translate these findings into therapeutic avenues, the researchers evaluated the efficacy of small-molecule inhibitors targeting taurine uptake via SLC6A6. Two structurally distinct taurine analogues, TAG (6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide hydrochloride) and GES (guanidinoethyl sulphonate), demonstrated potent inhibition of taurine transport in vitro. Treatment with these compounds significantly reduced colony formation by SLC6A6-competent mouse leukemia stem cells but had no effect on SLC6A6 knockout counterparts, affirming the specificity of action.

Notably, TAG and GES administration in primary human AML cells led to a pronounced suppression of colony-forming capacity, with reductions ranging from nearly two- to twenty-fold. These inhibitory effects were remarkably selective, as normal human hematopoietic stem and progenitor cells (HSPCs), characterized by CD34 positivity, were largely unharmed, indicating a therapeutic window that might minimize hematopoietic toxicity.

Given the clinical relevance of venetoclax and the frequent resistance that hampers its efficacy, the investigators probed whether combining venetoclax with taurine transporter inhibition could synergistically impair leukemic growth. The data were compelling: venetoclax alone decreased viability and colony formation in mouse LSCs, and when combined with either TAG or GES, the reduction in colony-forming units was not just additive but synergistic, with up to a 7.2-fold decrease observed. This synergy extended to primary human AML cells, where combined treatment induced colony formation reductions of up to 150-fold, a staggering potentiation relative to single-agent effects.

To circumvent the limitations of small-molecule inhibitors in vivo, particularly their inefficiency in fully blocking taurine uptake, the team employed shRNA-mediated knockdown of SLC6A6. This genetic approach confirmed that reducing SLC6A6 expression diminished taurine uptake by over two-fold and dramatically impaired colony formation in diverse myeloid malignancy cell lines, including blast crisis chronic myeloid leukemia (bcCML), AML, and myelodysplastic syndrome (MDS) models.

Critically, in patient-derived AML samples, SLC6A6 knockdown led to a 2.3- to more than 9-fold decrease in clonogenic potential without adversely affecting normal CD34+ HSPCs. This specificity was further validated in xenograft models, where SLC6A6 suppression curtailed the engraftment of primary human AML cells by up to 40-fold, while sparing normal hematopoietic progenitors. These findings outline a clear therapeutic window for targeting TAUT selectively in leukemic versus normal hematopoietic cells.

The implications of this work are profound. It delineates a previously underappreciated metabolic axis in AML pathogenesis, rooted in taurine uptake and utilization, and positions SLC6A6 as an attractive therapeutic target. By disrupting taurine-driven metabolic pathways, leukemic stem cells are rendered vulnerable, especially when combined with existing agents like venetoclax, opening new directions for treating drug-resistant AML.

This study exemplifies the power of integrating genomic, metabolic, and functional assays to uncover actionable targets in cancer stem cells, the elusive reservoir driving relapse and treatment failure. Future research will be required to optimize TAUT inhibitors for clinical use, elucidate the precise metabolic signaling downstream of taurine uptake, and explore combination regimens that may yield durable remissions in patients with aggressive myeloid leukemia.

Ultimately, targeting metabolic dependencies such as SLC6A6 provides a promising frontier in the war against AML, offering hope to patients whose disease no longer responds to conventional therapies. As the field advances, such targeted metabolic interventions may become staples in precision oncology, refining treatment paradigms and improving survival outcomes.

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Subject of Research: Taurine transporter SLC6A6’s role in acute myeloid leukemia metabolism and therapeutic resistance.

Article Title: Taurine from tumour niche drives glycolysis to promote leukaemogenesis.

Article References: Sharma, S., Rodems, B.J., Baker, C.D. et al. Taurine from tumour niche drives glycolysis to promote leukaemogenesis. Nature (2025). https://doi.org/10.1038/s41586-025-09018-7

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