Starving leukemia: nicotinamide phosphoribosyltransferase-dependent nicotinamide adenine dinucleotide salvage links metabolic vulnerability to therapeutic sensitivity in acute myeloid leukemia

Recently, Sanchez et al. provided evidence that nicotinamide phosphoribosyltransferase (NAMPT)-dependent nicotinamide adenine dinucleotide (NAD⁺) biosynthesis is a key survival axis in acute myeloid leukemia (AML), demonstrating that its inhibition reveals actionable co-dependencies in mitochondrial apoptosis and DNA-damage response pathways (1). In their analysis, single-cell RNA sequencing (RNA-seq) supported broad NAMPT expression across AML molecular subtypes, and proteomic profiling suggested that pharmacologic NAMPT inhibition with KPT-9274 triggers an adaptive survival response marked by B-cell lymphoma 2 (BCL2) upregulation. Functionally, BCL2 homology 3 (BH3) profiling demonstrated a hierarchy of anti-apoptotic dependence [BCL2 > myeloid cell leukemia 1 (MCL1) > B-cell lymphoma-extra large (BCL-xL)], providing a mechanistic bridge to rational combination strategies. Consistent with that framework, the authors report that combining KPT-9274 with a BCL2 inhibitor, venetoclax, synergistically amplifies mitochondrial dysfunction and accelerates apoptotic execution, supporting NAMPT inhibition as a sensitizing lever for BCL2 blockade. Beyond apoptosis, the authors further connect NAD⁺ depletion to nuclear vulnerabilities: NAMPT inhibition reportedly reduces poly (ADP-ribose) polymerase (PARP) activity, compromises DNA repair pathways, and thereby sensitizes AML cells to cytarabine and hypomethylating agents, broadening the translational reach from targeted therapy combinations to metabolic priming and precision medicine. Collectively, their work shifts the paradigm of NAMPT inhibition from a monotherapy approach to a context-amplifying strategy, revealing how core AML dependencies on NAD⁺ metabolism, mitochondrial priming, and DNA repair can be exploited as rational combination vulnerabilities (1).

This amplifier model integrates naturally with earlier NAMPT-focused AML studies, which established the biochemical and cellular consequences of NAD⁺ collapse and identified AML molecular subtypes and cellular compartments that may be most susceptible. Mitchell et al. first demonstrated broad preclinical activity of KPT-9274 [a p21-activated kinase 4 (PAK4)/NAMPT inhibitor with NAMPT-directed effects] across AML models, including reductions in mitochondrial respiration and glycolysis, induction of apoptosis, and mechanistic rescue consistent with NAD⁺ depletion as the dominant cytotoxic driver rather than PAK4 suppression. They also reported effects on functionally defined disease-propagating fractions (reduced colony formation and leukemia-initiating cell frequency) alongside comparatively limited toxicity toward normal hematopoietic cells in their systems, strengthening the original therapeutic premise that NAD⁺ stress might differentially pressure malignant programs (2). Subedi et al. subsequently sharpened this concept at the stem-cell level by identifying NAMPT inhibitors in a metabolic screen as selective killers of AML leukemic stem cells (LSCs) while sparing normal hematopoietic stem/progenitor cells, and by providing a mechanistic rationale rooted in lipid homeostasis disruption: NAMPT inhibition suppressed saturated fatty acids to monounsaturated fatty acids conversion [via stearoyl-CoA desaturase (SCD)], eliciting apoptosis and provoking a compensatory transcriptional response involving sterol regulatory element-binding protein (SREBP)-regulated genes that partially protected LSCs. They further demonstrated that blocking SREBP signaling (with dipyridamole) enhanced NAMPT-inhibitor cytotoxicity in vivo, suggesting that resistance can emerge not only from metabolic rewiring, but also from definable compensatory circuits that may be druggable (3). In this context, the adaptive increase in BCL2 identified by Sanchez et al. can be viewed as a specific example of a broader AML survival strategy, in which NAD⁺ stress prompts dynamic reallocation of survival resources, spanning anti-apoptotic buffering, membrane/lipid remodeling, and other NAD⁺-sensitive processes, thereby revealing opportunities for multi-node therapeutic intervention.

Using acquired venetoclax-resistant (VR) AML cell models, we previously demonstrated divergent metabolic rewiring, a glycolysis-biased state in MV4-11VR versus increased oxidative phosphorylation (OXPHOS) in MOLM-13VR. Despite sharing FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and lysine methyltransferase 2A (KMT2A) rearrangements, these models show that metabolic shifts are not dictated solely by molecular background; nonetheless, they converge on shared signaling adaptations, most notably phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR). Critically, despite metabolic heterogeneity, targeting metabolism re-sensitized resistant cells; both metformin (an antidiabetic drug that inhibits mitochondrial respiratory chain complex I) and KPT-9274 restored venetoclax responsiveness, and combinations produced strong synergy with near-complete cell death (4). We previously demonstrated this heterogeneity-with-convergence theme in AML patients displaying high mitochondrial DNA (mtDNA) content, which identified OXPHOS-driven AML and is associated with increased sensitivity to metformin and other mitochondrial inhibitors. Notably, we also highlight NAMPT activation as an adaptive brake on mitochondrial inhibitor activity and show that combining metformin with KPT-9274 enhances sensitivity and overcomes this metabolic adaptation (5). Taken together, a coherent translational narrative emerges: NAMPT inhibition can (I) prime mitochondria for apoptosis and (II) reduce DNA repair capacity, while AML, especially under venetoclax pressure, may oscillate between bioenergetic states yet remain dependent on NAD⁺-supported buffering systems. This convergence suggests that NAMPT inhibition is not merely another metabolic drug, but a candidate integration node capable of connecting apoptotic priming (venetoclax), energetic collapse (mitochondrial inhibitors), epigenetic modulators (hypomethylating agents), and genotoxic stress [cytarabine (Ara-C)] into a mechanistically consistent combination framework.

Recent studies suggest that NAMPT haploinsufficiency in -7/-7q-deleted diseases confers a “collateral lethality” vulnerability, increasing cellular dependence on residual NAMPT activity and sensitizing malignant cells to its pharmacologic inhibition (6). Concurrently, the primary bypass route for NAD⁺ salvage, the nicotinic acid pathway, is governed by nicotinate phosphoribosyltransferase (NAPRT) (located at 8q24.3). Copy-number alterations or epigenetic silencing at this locus can impair nicotinic acid-mediated rescue during NAMPT inhibition (7,8). Specifically, NAPRT promoter methylation predicts the loss of this rescue capacity, serving as a critical biomarker for stratifying patients in NAMPT-inhibitor therapeutic strategies (7). This translational framework is further reinforced by emerging pre-leukemic data. Recent findings demonstrate that high-risk MDS stem and progenitor cells are functionally dependent on nicotinamide salvage, while independent evidence confirms the selective sensitivity of monosomy 7/7q-deleted myelodysplastic syndromes (MDS) to NAMPT inhibition. Consistent with the aforementioned gene-dosage effects, these observations underscore that NAMPT vulnerability is manifested before the progression to overt AML (9,10). Collectively, these data support the rationale for early, risk-adapted interventions within molecularly defined genetic contexts. Beyond genetic dosage, the state of cellular differentiation emerges as a critical determinant of therapeutic response. Compelling evidence suggests that tumor-supportive, M2-like AML-associated macrophages (AAMs) significantly upregulate NAMPT, rendering them preferentially vulnerable to the KPT-9274 and E-Daporinad inhibitors (11). Ex vivo screenings reveal that AAM-enriched samples, which often exhibit relative resistance to Ara-C and venetoclax, remain highly sensitive to NAMPT inhibition. This sensitivity is driven by a profound depletion of NAD⁺ levels and a subsequent collapse of mitochondrial respiration within these differentiated myeloid compartments (11). Collectively, the convergence of pathway-specific gene dosage (NAMPT/NAPRT) and differentiation-linked metabolic dependencies (AAM/M2 programs) highlights that comprehensive biomarker mapping is not merely secondary. Instead, it is central to predicting and rationally extending NAMPT-inhibitor efficacy across the AML-MDS continuum.

The key question, then, is how to convert these preclinical signals into clinically navigable strategies with biomarker discipline and an explicit resistance-management plan. At the mechanistic level, NAMPT sits at a crossroads: it is widely described as a rate-limiting enzyme in NAD⁺ regeneration, and NAD⁺ depletion is linked to mitochondrial dysfunction and DNA damage biology, exactly the two vulnerability axes leveraged by Sanchez et al. (apoptosis priming; PARP/repair impairment) (1,12). But the same centrality creates multiple escape routes, and resistance is not hypothetical. Reviews focused on NAMPT inhibitor resistance emphasize that, although NAMPT is frequently overexpressed across cancers and pharmacologic targeting can be effective in some settings, drug resistance remains a major concern, motivating combination strategies and careful patient selection (13). As a final context for this commentary, we propose a practical outlook grounded in the aforementioned data: (I) context definition, identify AML subsets most likely to experience synthetic lethal NAD⁺ stress (e.g., transcriptionally NAMPT-high across subtypes per single-cell analysis; functionally OXPHOS-driven or metabolically states such as high mtDNA/OXPHOS programs); (II) mechanism-matched combinations, pairing NAMPT inhibitors with agents that exploit the expected adaptive response (venetoclax for BCL2 upshift; SREBP-axis disruption, where lipid remodeling buffers NAMPT stress; mitochondrial inhibitors, where NAD⁺ salvage supports respiratory adaptation; and standard genotoxic therapies, where repair impairment is demonstrable); (III) resistance surveillance, prospectively track compensatory pathways implicated by the literature (anti-apoptotic rewiring, lipid homeostasis programs, and broader NAD⁺ network adjustments) and adapt regimens before overt clinical resistance. Importantly, this is not an argument for maximalism, but for rational biomarker screening and patient selection. Sanchez et al. (1) provide the rationale for NAMPT inhibition as a sensitizer to both venetoclax and chemotherapy, while the earlier AML NAMPT studies supply orthogonal validation that NAD⁺ stress intersects with stemness, mitochondrial state, and relapse biology in ways that can be therapeutically exploited (Figure 1).

Figure 1 The NAMPT inhibitor as a context amplifier and therapeutic sensitization node in AML. Schematic overview of how KPT-9274-mediated NAMPT inhibition collapses the NAD⁺ salvage pathway, leading to intracellular NAD⁺ depletion that unmasks three convergent vulnerability axes. Axis A (mitochondrial priming/apoptosis): NAD⁺ stress drives adaptive BCL2 upregulation and a shift toward BCL2-dominant anti-apoptotic dependence, creating an exploitable window in which venetoclax further amplifies mitochondrial dysfunction and accelerates apoptosis. Axis B (nuclear vulnerability/DNA repair): NAD⁺ depletion reduces PARP activity, compromising DNA repair and increasing genomic fragility, thereby sensitizing cells to Ara-C and HMA. Axis C (LSC metabolism/lipid homeostasis): NAMPT inhibition preferentially impacts LSCs by disrupting lipid homeostasis, including impaired saturated-to-monounsaturated fatty acid conversion via SCD, with compensatory SREBP signaling that may be attenuated by dipyridamole. In clinically relevant contexts, VR AML, often characterized by hyperactive PI3K/AKT/mTOR signaling, can remain vulnerable to NAD⁺ depletion, and combined metabolic targeting (e.g., metformin plus NAD⁺ blockade) may overcome high-OXPHOS/mtDNA-driven adaptation. Overall, NAMPT inhibition integrates apoptotic priming, energetic collapse, and genotoxic stress to promote cell death, LSC elimination, and reversal of acquired resistance. The figure was created by the authors using the Gemini tool (https://gemini.google.com/). AML, acute myeloid leukemia; Ara-C, cytarabine; BCL2, B-cell lymphoma 2; DSB, double-strand break; HMA, hypomethylating agent; LSC, leukemic stem cell; MCL1, myeloid cell leukemia 1; mtDNA, mitochondrial DNA; NAD⁺, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyltransferase; OXPHOS, oxidative phosphorylation; PARP, poly(ADP-ribose) polymerase; PI3K/AKT/mTOR, phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin; SCD, stearoyl-CoA desaturase; SREBP, sterol regulatory element-binding protein.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0292/prf

Funding: This study was supported by the São Paulo Research Foundation (FAPESP) (grants 2024/21624-7 and 2023/12246-6). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES), Finance Code 001.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0292/coif). J.A.M.N. serves as an unpaid editorial board member of Translational Cancer Research from August 2025 to September 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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