NAMPT and NAPRT1: novel polymorphisms and distribution of variants between normal tissues and tumor samples

Duarte-Pereira, Sara; Silva, Sarah S.; Azevedo, Luı́sa; Castro, Luísa; Amorim, António; Silva, Raquel M.

doi:10.1038/srep06311

Cited by 23 publications

(23 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3). We also noted a germline duplication in NAPRT1, a major enzyme in cellular metabolism 52 , in one additional family (FML064, p.Val216_Phe219dup), highlighting its candidacy as it was previously found to be mutated (p. Arg405*) in the affected members of an MDS/AML family described by Patnaik et al 41 (Fig. 3; Supplementary Data 8).…”

Section: Resultssupporting

confidence: 51%

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

et al. 2020

View full text Add to dashboard Cite

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.

show abstract

Section: Resultssupporting

confidence: 51%

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In addition to developing rational combination regimens using NAMPT inhibitors, careful patient selection represents an additional opportunity to maximize the efficacy of these agents. For example, IDH mutant cancers have been shown to have exquisite sensitivity to NAMPT inhibitors (63)(64)(65), as have tumors deficient in NAPRT (9,(145)(146)(147)(148)(149)(150)(151). Patient selection may also be guided by recognition of specific vulnerabilities in the non-metabolic pathways supported by NAMPT, such as HR-deficiency or EMT targeting for metastatic disease.…”

Section: Discussionmentioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

View full text Add to dashboard Cite

Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

show abstract

“…Some genetic polymorphisms were identified in the human NAMPT gene, potentially responsible for NAMPT expression. Different representation of these Single Nucleotide Polymorphisms (SNPs) were described in patients with acute respiratory distress syndrome, type 2 diabetes, glucose and lipid metabolism alterations, diastolic blood pressure and hypertensive disorders compared to controls (107).…”

Section: Namptmentioning

confidence: 99%

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

2020

View full text Add to dashboard Cite

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are two intracellular enzymes that catalyze the first step in the biosynthesis of NAD from nicotinamide and nicotinic acid, respectively. By fine tuning intracellular NAD levels, they are involved in the regulation/reprogramming of cellular metabolism and in the control of the activity of NAD-dependent enzymes, including sirtuins, PARPs, and NADases. However, during evolution they both acquired novel functions as extracellular endogenous mediators of inflammation. It is well-known that cellular stress and/or damage induce release in the extracellular milieu of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs), which modulate immune functions through binding pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), and activate inflammatory responses. Increasing evidence suggests that extracellular (e)NAMPT and eNAPRT are novel soluble factors with cytokine/adipokine/DAMP-like actions. Elevated eNAMPT were reported in several metabolic and inflammatory disorders, including obesity, diabetes, and cancer, while eNAPRT is emerging as a biomarker of sepsis and septic shock. This review will discuss available data concerning the dual role of this unique family of enzymes.

show abstract

NAMPT and NAPRT1: novel polymorphisms and distribution of variants between normal tissues and tumor samples

Cited by 23 publications

References 53 publications

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

Contact Info

Product

Resources

About