Publications by authors named "Silvia Deaglio"

138 Publications

A novel COLEC10 mutation in a child with 3MC syndrome.

Eur J Med Genet 2021 Dec 2;64(12):104374. Epub 2021 Nov 2.

Department of Medical Sciences, University of Turin, Turin, Italy; Immunogenetics and Transplant Biology Service, Città della Salute e della Scienza University Hospital, Turin, Italy. Electronic address:

3MC syndrome is an autosomal recessive disorder encompassing four rare disorders previously known as the Malpuech, Michels, Mingarelli and Carnevale syndromes. They are characterized by a variable spectrum of abnormalities, including facial dysmorphisms, along with genital, limb and vesico-renal anomalies. The syndrome was originally attributed to mutations in MASP1 and COLEC11, which code for proteins involved in the lectin complement pathway. More recently, mutations in COLEC10, a third gene coding for collectin CL-L1, were identified in a limited number of patients with 3MC syndrome. Here we describe a 4-years-old patient with typical 3MC phenotypic characteristics, including blepharophimosis, telecanthus, high arched eyebrows, fifth finger clinodactyly, sacral dimple and horseshoe kidney. Initial genetic analysis was based on clinical exome sequencing, where only MASP1 and COLEC11 genes are present, without evidence of pathogenic variants. Sanger sequencing of COLEC10 identified the homozygous frameshift variant c.807_810delCTGT; p.Cys270Serfs*33, which results in the loss of the natural stop codon. The resulting protein is 24 amino acids longer and lacks a conserved cysteine residue (Cys270), which could affect protein folding. Segregation studies confirmed that both parents were carriers for the variant: interestingly they originate from the same area of Apulia in southern Italy. Plasma levels of CL-L1 in the patient and her parents were within normal range, suggesting that this variant does not modify transcription or secretion. However, the variant affects the chemo-attractive feature of CL-L1, as HeLa cells migrate significantly less in response to the mutant protein compared to the wild-type one.
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http://dx.doi.org/10.1016/j.ejmg.2021.104374DOI Listing
December 2021

The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy.

Orphanet J Rare Dis 2021 09 4;16(1):374. Epub 2021 Sep 4.

Division of Thoracic Surgery and Lung Transplantation, Department for the Treatment and Study of Cardiothoracic Diseases and Cardiothoracic Transplantation, IRCCS-ISMETT, Palermo, Italy.

Background: Rare diseases are chronic and life-threatening disorders affecting < 1 person every 2,000. For most of them, clinical symptoms and signs can be observed at birth or childhood. Approximately 80% of all rare diseases have a genetic background and most of them are monogenic conditions. In addition, while the majority of these diseases is still incurable, early diagnosis and specific treatment can improve patients' quality of life. Transplantation is among the therapeutic options and represents the definitive treatment for end-stage organ failure, both in children and adults. The aim of this paper was to analyze, in a large cohort of Italian patients, the main rare genetic diseases that led to organ transplantation, specifically pointing the attention on the pediatric cohort.

Results: To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002-2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants.

Conclusions: This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children.
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http://dx.doi.org/10.1186/s13023-021-02013-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418291PMC
September 2021

The Extracellular NADome Modulates Immune Responses.

Front Immunol 2021 4;12:704779. Epub 2021 Aug 4.

Laboratory of Cancer Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy.

The term NADome refers to the intricate network of intracellular and extracellular enzymes that regulate the synthesis or degradation of nicotinamide adenine dinucleotide (NAD) and to the receptors that engage it. Traditionally, NAD was linked to intracellular energy production through shuffling electrons between oxidized and reduced forms. However, recent data indicate that NAD, along with its biosynthetic and degrading enzymes, has a life outside of cells, possibly linked to immuno-modulating non-enzymatic activities. Extracellular NAD can engage puriginergic receptors triggering an inflammatory response, similar - to a certain extent - to what described for adenosine triphosphate (ATP). Likewise, NAD biosynthetic and degrading enzymes have been amply reported in the extracellular space, where they possess both enzymatic and non-enzymatic functions. Modulation of these enzymes has been described in several acute and chronic conditions, including obesity, cancer, inflammatory bowel diseases and sepsis. In this review, the role of the extracellular NADome will be discussed, focusing on its proposed role in immunomodulation, together with the different strategies for its targeting and their potential therapeutic impact.
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http://dx.doi.org/10.3389/fimmu.2021.704779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371318PMC
August 2021

HLA-DRB1 mismatch-based identification of donor-derived cell free DNA (dd-cfDNA) as a marker of rejection in heart transplant recipients: A single-institution pilot study.

J Heart Lung Transplant 2021 08 14;40(8):794-804. Epub 2021 May 14.

Department of Medical Sciences, University of Turin, Turin, Italy; Immunogenetics and Transplant Biology Service, Città della Salute e della Scienza University Hospital, Turin, Italy.

Background: Donor-derived cell-free DNA (dd-cfDNA) is considered a reliable marker of organ damage with potential applications in the follow-up of transplant recipients.

Methods: In this work we present an assay based on the donor-recipient HLA-mismatch (human leukocyte antigen) at the HLA-DRB1 locus to monitor rejection by quantifying the percentage of dd-cfDNA using a droplet digital PCR (polymerase chain reaction) technique. A panel of probes targeting the HLA-DRB1 locus and covering >85% genetic variability was validated and used to assess dd-cfDNA levels in a prospective cohort of 19 adult heart transplant recipients (mean age 50.9±14.8 years). The assay was carried out on a total of 232 liquid biopsies collected at the same time as endomyocardial biopsy (EMB) during routine post-transplant follow-up.

Results: Results show a significant increase of dd-cfDNA related to ischemia-reperfusion injury (2.22±2.09%) and to acute cellular rejection (1.71±3.10%) compared to stable conditions (0.43±1.04%, p < 0.0001). On the contrary, no increase was observed during infections or vascular complications, underlining the potential role of this biomarker for rejection monitoring. With a cut-off of 0.11%, the test showed 70.8% specificity (95% CI, 58.17% - 81.40%) and 64.2% sensitivity (95% CI, 49.80% - 76.86%) in discriminating acute rejection from no rejection.

Conclusions: These data demonstrate that this HLA mismatch-based droplet digital PCR method is effective for monitoring rejection in heart transplant recipients. Compared to next generation sequencing approaches, it is far more flexible, less expensive and provides faster results.
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http://dx.doi.org/10.1016/j.healun.2021.05.001DOI Listing
August 2021

The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation.

Cell Rep 2021 Jun;35(11):109252

Molecular Biotechnology Center (MBC), Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Electronic address:

Heme is an iron-containing porphyrin of vital importance for cell energetic metabolism. High rates of heme synthesis are commonly observed in proliferating cells. Moreover, the cell-surface heme exporter feline leukemia virus subgroup C receptor 1a (FLVCR1a) is overexpressed in several tumor types. However, the reasons why heme synthesis and export are enhanced in highly proliferating cells remain unknown. Here, we illustrate a functional axis between heme synthesis and heme export: heme efflux through the plasma membrane sustains heme synthesis, and implementation of the two processes down-modulates the tricarboxylic acid (TCA) cycle flux and oxidative phosphorylation. Conversely, inhibition of heme export reduces heme synthesis and promotes the TCA cycle fueling and flux as well as oxidative phosphorylation. These data indicate that the heme synthesis-export system modulates the TCA cycle and oxidative metabolism and provide a mechanistic basis for the observation that both processes are enhanced in cells with high-energy demand.
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http://dx.doi.org/10.1016/j.celrep.2021.109252DOI Listing
June 2021

B-cell receptor signaling and genetic lesions in TP53 and CDKN2A/CDKN2B cooperate in Richter transformation.

Blood 2021 09;138(12):1053-1066

Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy.

B-cell receptor (BCR) signals play a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL), but their role in regulating CLL cell proliferation has still not been firmly established. Unlike normal B cells, CLL cells do not proliferate in vitro upon engagement of the BCR, suggesting that CLL cell proliferation is regulated by other signals from the microenvironment, such as those provided by Toll-like receptors or T cells. Here, we report that BCR engagement of human and murine CLL cells induces several positive regulators of the cell cycle, but simultaneously induces the negative regulators CDKN1A, CDKN2A, and CDKN2B, which block cell-cycle progression. We further show that introduction of genetic lesions that downregulate these cell-cycle inhibitors, such as inactivating lesions in CDKN2A, CDKN2B, and the CDKN1A regulator TP53, leads to more aggressive disease in a murine in vivo CLL model and spontaneous proliferation in vitro that is BCR dependent but independent of costimulatory signals. Importantly, inactivating lesions in CDKN2A, CDKN2B, and TP53 frequently co-occur in Richter syndrome (RS), and BCR stimulation of human RS cells with such lesions is sufficient to induce proliferation. We also show that tumor cells with combined TP53 and CDKN2A/2B abnormalities remain sensitive to BCR-inhibitor treatment and are synergistically sensitive to the combination of a BCR and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor both in vitro and in vivo. These data provide evidence that BCR signals are directly involved in driving CLL cell proliferation and reveal a novel mechanism of Richter transformation.
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http://dx.doi.org/10.1182/blood.2020008276DOI Listing
September 2021

Targeting Adenosine with Adenosine Deaminase 2 to Inhibit Growth of Solid Tumors.

Cancer Res 2021 06 16;81(12):3319-3332. Epub 2021 Apr 16.

Formerly of Halozyme Therapeutics, Inc., San Diego, California.

Extracellular adenosine in tumors can suppress immune responses and promote tumor growth. Adenosine deaminase 2 (ADA2) converts adenosine into inosine. The role of ADA2 in cancer and whether it can target adenosine for cancer therapy has not been investigated. Here we show that increased ADA2 expression is associated with increased patient survival and enrichment of adaptive immune response pathways in several solid tumor types. Several ADA2 variants were created to improve catalytic efficiency, and PEGylation was used to prolong systemic exposure. In mice, PEGylated ADA2 (PEGADA2) inhibited tumor growth by targeting adenosine in an enzyme activity-dependent manner and thereby modulating immune responses. These findings introduce endogenous ADA2 expression as a prognostic factor and PEGADA2 as a novel immunotherapy for cancer. SIGNIFICANCE: This study identifies ADA2 as a prognostic factor associated with prolonged cancer patient survival and introduces the potential of enzymatic removal of adenosine with engineered ADA2 for cancer immunotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0340DOI Listing
June 2021

Synergistic efficacy of the dual PI3K-δ/γ inhibitor duvelisib with the Bcl-2 inhibitor venetoclax in Richter syndrome PDX models.

Blood 2021 06;137(24):3378-3389

Department of Medical Sciences, University of Turin, Turin, Italy.

A small subset of cases of chronic lymphocytic leukemia undergoes transformation to diffuse large B-cell lymphoma, Richter syndrome (RS), which is associated with a poor prognosis. Conventional chemotherapy results in limited responses, underlining the need for novel therapeutic strategies. Here, we investigate the ex vivo and in vivo efficacy of the dual phosphatidylinositol 3-kinase-δ/γ (PI3K-δ/γ) inhibitor duvelisib (Duv) and the Bcl-2 inhibitor venetoclax (Ven) using 4 different RS patient-derived xenograft (PDX) models. Ex vivo exposure of RS cells to Duv, Ven, or their combination results in variable apoptotic responses, in line with the expression levels of target proteins. Although RS1316, IP867/17, and RS9737 cells express PI3K-δ, PI3K-γ, and Bcl-2 and respond to the drugs, RS1050 cells, expressing very low levels of PI3K-γ and lacking Bcl-2, are fully resistant. Moreover, the combination of these drugs is more effective than each agent alone. When tested in vivo, RS1316 and IP867/17 show the best tumor growth inhibition responses, with the Duv/Ven combination leading to complete remission at the end of treatment. The synergistic effect of Duv and Ven relies on the crosstalk between PI3K and apoptotic pathways occurring at the GSK3β level. Indeed, inhibition of PI3K signaling by Duv results in GSK3β activation, leading to ubiquitination and subsequent degradation of both c-Myc and Mcl-1, making RS cells more sensitive to Bcl-2 inhibition by Ven. This work provides, for the first time, a proof of concept of the efficacy of dual targeting of PI3K-δ/γ and Bcl-2 in RS and providing an opening for a Duv/Ven combination for these patients. Clinical studies in aggressive lymphomas, including RS, are under way. This trial was registered at www.clinicaltrials.gov as #NCT03892044.
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http://dx.doi.org/10.1182/blood.2020010187DOI Listing
June 2021

Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes.

J Am Soc Nephrol 2021 05 15;32(5):1114-1130. Epub 2021 Mar 15.

Department of Medical Sciences, University of Turin, Turin, Italy.

Background: Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored.

Methods: We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy).

Results: Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. , M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury.

Conclusions: These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued TNT-mediated horizontal transfer may open new avenues of research.
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http://dx.doi.org/10.1681/ASN.2020071076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259684PMC
May 2021

ROR1 targeting with the antibody-drug conjugate VLS-101 is effective in Richter syndrome patient-derived xenograft mouse models.

Blood 2021 06;137(24):3365-3377

Department of Medical Sciences, University of Torino, Turin, Italy.

Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL), typically to an aggressive lymphoma. Treatment options for RS are limited and the disease is often fatal. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed on CLL cells and other cancers but not on healthy adult tissues, making it an attractive, tumor-specific therapeutic target. VLS-101 is being developed as an antibody-drug conjugate (ADC) for therapy of ROR1-expressing (ROR1+) cancers. VLS-101 comprises UC-961 (a humanized immunoglobulin G1 monoclonal antibody that binds an extracellular epitope of human ROR1), a maleimidocaproyl-valine-citrulline-para-aminobenzoate linker, and the antimicrotubule cytotoxin monomethyl auristatin E (MMAE). VLS-101 binding to ROR1 results in rapid cellular internalization and delivery of MMAE to induce tumor cell death. We studied 4 RS patient-derived xenografts (RS-PDXs) with varying levels of ROR1 expression (11%, 32%, 85%, and 99% of cells). VLS-101 showed no efficacy in the lowest-expressing RS-PDX but induced complete remissions in those with higher levels of ROR1 expression. Responses were maintained during the posttherapy period, particularly after higher VLS-101 doses. In systemic ROR1+ RS-PDXs, VLS-101 dramatically decreased tumor burden in all RS-colonized tissues and significantly prolonged survival. Animals showed no adverse effects or weight loss. Our results confirm ROR1 as a target in RS and demonstrate the therapeutic potential of using an ADC directed toward ROR1 for the treatment of hematological cancers. A phase 1 clinical trial of VLS-101 (NCT03833180) is ongoing in patients with RS and other hematological malignancies.
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http://dx.doi.org/10.1182/blood.2020008404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212514PMC
June 2021

Evaluation of Graft Fibrosis, Inflammation and Donor-specific Antibodies at Protocol Liver Biopsies in Pediatric Liver Transplant Patients: a Single Center Experience.

Transplantation 2021 Jan 25. Epub 2021 Jan 25.

Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Turin, Italy Pathology Unit, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Turin, Italy Regional Transplant Center, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Turin, Italy Radiology Unit, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Turin, Italy Immunogenetics and transplant biology service, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Turin, Italy General Surgery, Liver Transplant Center, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.

Background: The impact of graft fibrosis and inflammation on the natural history of pediatric liver transplants (LT) is still debated. Our objectives were to evaluate the evolution of posttransplant fibrosis and inflammation over time at protocol liver biopsies (PLBs), risk factors for fibrosis, presence of donor-specific antibodies (DSAs) and/or their correlation with graft and recipient factors.

Methods: A single-center, retrospective (2000-2019) cross-sectional study on pediatric LT recipients who had at least one PLB, followed by a longitudinal evaluation in those who had at least two PLBs, was conducted. Fibrosis was assessed by the Liver Allograft Fibrosis Semiquantitative score, inflammation by the Rejection Activity Index, DSAs by Luminex®.

Results: A total of 134 PLBs from 94 patients were included. Fibrosis was detected in 87% (30% mild, 45% moderate, 12% severe), 80% in the portal tracts. There was an increase in fibrosis between the 1-3 and the 4-6 year group (p=0.01), then it was stable. Inflammation was observed in 44% (30% mild, 13% moderate, 1% severe), 90% in the portal tracts. Anti-HLA II (IgG) DSAs were detected in 14/40 (35%). Portal fibrosis was associated with portal inflammation in the 1-3 year group (p=0.04). Low immunosuppression levels were correlated with sinusoidal fibrosis (p=0.04) and DSA positivity (p-value=0.006). There was no statistically significant correlation between DSA positivity and the presence of graft fibrosis or inflammation.

Conclusions: This study corroborates the concept of an early evolution of silent graft fibrosis. Suboptimal immunosuppression may play a role in the development of fibrosis and DSAs.
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http://dx.doi.org/10.1097/TP.0000000000003649DOI Listing
January 2021

NAMPT Over-Expression Recapitulates the BRAF Inhibitor Resistant Phenotype Plasticity in Melanoma.

Cancers (Basel) 2020 Dec 20;12(12). Epub 2020 Dec 20.

Cancer Immunogenetics Lab, Department of Medical Sciences, University of Turin, 10126 Turin, Italy.

Serine-threonine protein kinase B-RAF -mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a driving factor in BRAFi resistance development. Using stable and inducible NAMPT over-expression systems, we showed that forced NAMPT expression in MM -mutated cell lines led to increased energy production, MAPK activation, colony-formation capacity, and enhance tumorigenicity in vivo. Moreover, NAMPT over-expressing cells switched toward an invasive/mesenchymal phenotype, up-regulating expression of ZEB1 and TWIST, two transcription factors driving the epithelial to mesenchymal transition (EMT) process. Consistently, within the NAMPT-overexpressing cell line variants, we observed an increased percentage of a rare, drug-effluxing stem cell-like side population (SP) of cells, paralleled by up-regulation of ABCC1/MRP1 expression and CD133-positive cells. The direct correlation between NAMPT expression and gene set enrichments involving metastasis, invasiveness and mesenchymal/stemness properties were verified also in melanoma patients by analyzing The Cancer Genome Atlas (TCGA) datasets. On the other hand, CRISPR/Cas9 full knock-out BRAFi-resistant MM cells are not viable, while inducible partial silencing drastically reduces tumor growth and aggressiveness. Overall, this work revealed that NAMPT over-expression is both necessary and sufficient to recapitulate the BRAFi-resistant phenotype plasticity.
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http://dx.doi.org/10.3390/cancers12123855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766175PMC
December 2020

CD200 and Chronic Lymphocytic Leukemia: Biological and Clinical Relevance.

Front Oncol 2020 26;10:584427. Epub 2020 Nov 26.

Hematology Institute, IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.

CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin protein superfamily, is broadly expressed on a wide variety of cell types, such as B lymphocytes, a subset of T lymphocytes, dendritic cells, endothelial and neuronal cells. It delivers immunosuppressive signals through its receptor CD200R, which is expressed on monocytes/myeloid cells and T lymphocytes. Moreover, interaction of CD200 with CD200R has also been reported to play a role in the regulation of tumor immunity. Overexpression of CD200 has been reported in chronic lymphocytic leukemia (CLL) and hairy cell leukemia but not in mantle cell lymphoma, thus helping to better discriminate between these different B cell malignancies with different prognosis. In this review, we focus on the role of CD200 expression in the differential diagnosis of mature B-cell neoplasms and on the prognostic significance of CD200 expression in CLL, where conflicting results have been published so far. Of interest, increasing evidences indicate that anti-CD200 treatment might be therapeutically beneficial for treating CD200-expressing malignancies, such as CLL.
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http://dx.doi.org/10.3389/fonc.2020.584427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727446PMC
November 2020

Clinical exome sequencing is a powerful tool in the diagnostic flow of monogenic kidney diseases: an Italian experience.

J Nephrol 2021 10 23;34(5):1767-1781. Epub 2020 Nov 23.

Department of Medical Sciences, University of Turin, via Santena 19, 10126, Turin, Italy.

Background: A considerable minority of patients on waiting lists for kidney transplantation either have no diagnosis (and fall into the subset of undiagnosed cases) because kidney biopsy was not performed or histological findings were non-specific, or do not fall into any well-defined clinical category. Some of these patients might be affected by a previously unrecognised monogenic disease.

Methods: Through a multidisciplinary cooperative effort, we built an analytical pipeline to identify patients with chronic kidney disease (CKD) with a clinical suspicion of a monogenic condition or without a well-defined diagnosis. Following the stringent phenotypical and clinical characterization required by the flowchart, candidates meeting these criteria were further investigated by clinical exome sequencing followed by in silico analysis of 225 kidney-disease-related genes.

Results: By using an ad hoc web-based platform, we enrolled 160 patients from 13 different Nephrology and Genetics Units located across the Piedmont region over 15 months. A preliminary "remote" evaluation based on well-defined inclusion criteria allowed us to define eligibility for NGS analysis. Among the 138 recruited patients, 52 (37.7%) were children and 86 (62.3%) were adults. Up to 48% of them had a positive family history for kidney disease. Overall, applying this workflow led to the identification of genetic variants potentially explaining the phenotype in 78 (56.5%) cases.

Conclusions: These results underline the importance of clinical exome sequencing as a versatile and highly useful, non-invasive tool for genetic diagnosis of kidney diseases. Identifying patients who can benefit from targeted therapies, and improving the management of organ transplantation are further expected applications.
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http://dx.doi.org/10.1007/s40620-020-00898-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494711PMC
October 2021

HLA and AB0 Polymorphisms May Influence SARS-CoV-2 Infection and COVID-19 Severity.

Transplantation 2021 01;105(1):193-200

National Transplant Center, Istituto Superiore di Sanità, Roma, Italy.

Background: SARS-CoV-2 infection is heterogeneous in clinical presentation and disease evolution. To investigate whether immune response to the virus can be influenced by genetic factors, we compared HLA and AB0 frequencies in organ transplant recipients and waitlisted patients according to presence or absence of SARS-CoV-2 infection.

Methods: A retrospective analysis was performed on an Italian cohort composed by transplanted and waitlisted patients in a January 2002 to March 2020 time frame. Data from this cohort were merged with the Italian registry of COVID+ subjects, evaluating infection status of transplanted and waitlisted patients. A total of 56 304 cases were studied with the aim of comparing HLA and AB0 frequencies according to the presence (n = 265, COVID+) or absence (n = 56 039, COVID-) of SARS-CoV-2 infection.

Results: The cumulative incidence rate of COVID-19 was 0.112% in the Italian population and 0.462% in waitlisted/transplanted patients (OR = 4.2; 95% CI, 3.7-4.7; P < 0.0001). HLA-DRB1*08 was more frequent in COVID+ (9.7% and 5.2%: OR = 1.9, 95% CI, 1.2-3.1; P = 0.003; Pc = 0.036). In COVID+ patients, HLA-DRB1*08 was correlated to mortality (6.9% in living versus 17.5% in deceased: OR = 2.9, 95% CI, 1.15-7.21; P = 0.023). Peptide binding prediction analyses showed that these DRB1*08 alleles were unable to bind any of the viral peptides with high affinity. Finally, blood group A was more frequent in COVID+ (45.5%) than COVID- patients (39.0%; OR = 1.3; 95% CI, 1.02-1.66; P = 0.03).

Conclusions: Although preliminary, these results suggest that HLA antigens may influence SARS-CoV-2 infection and clinical evolution of COVID-19 and confirm that blood group A individuals are at greater risk of infection, providing clues on the spread of the disease and indications about infection prognosis and vaccination strategies.
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http://dx.doi.org/10.1097/TP.0000000000003507DOI Listing
January 2021

The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas.

Int J Mol Sci 2020 Sep 21;21(18). Epub 2020 Sep 21.

Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

The tumor microenvironment plays a crucial role in driving the behavior and the aggressiveness of neoplastic cells [...].
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http://dx.doi.org/10.3390/ijms21186915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555678PMC
September 2020

Targeting of the A2A adenosine receptor counteracts immunosuppression in vivo in a mouse model of chronic lymphocytic leukemia.

Haematologica 2021 05 1;106(5):1343-1353. Epub 2021 May 1.

Lab of Cancer Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy.

Tumor immunosuppression is a major cause for treatment failure and disease relapse, both in solid tumors and leukemia. Local hypoxia is among the conditions that cause immunosuppression, acting at least in part through the upregulation of extracellular adenosine levels, which potently suppress T cell responses and skew macrophages towards an M2 phenotype. Hence, there is intense investigation to identify drugs that target this axis. By using the TCL1 adoptive transfer CLL mouse model, we show that adenosine production and signaling are upregulated in the hypoxic lymphoid niches, where intense colonization of leukemic cells occurs. This leads to a progressive remodeling of the immune system towards tolerance, with expansion of T regulatory cells (Tregs), loss of CD8+ T cell cytotoxicity and differentiation of murine macrophages towards the patrolling (M2-like) subset. In vivo administration of SCH58261, an inhibitor the A2A adenosine receptor, re-awakens T cell responses, while limiting Tregs expansion, and re-polarizes monocytes towards the inflammatory (M1-like) phenotype. These results show for the first time the in vivo contribution of adenosine signaling to immune tolerance in CLL, and the translational implication of drugs interrupting this pathway. Although the effects of SCH58261 on leukemic cells are limited, interfering with adenosine signaling may represent an appealing strategy for combination-based therapeutic approaches.
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http://dx.doi.org/10.3324/haematol.2019.242016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094100PMC
May 2021

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

Front Oncol 2020 19;10:358. Epub 2020 Mar 19.

Laboratory of Tumor Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy.

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.
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http://dx.doi.org/10.3389/fonc.2020.00358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096376PMC
March 2020

Vitamin C Restricts the Emergence of Acquired Resistance to EGFR-Targeted Therapies in Colorectal Cancer.

Cancers (Basel) 2020 Mar 14;12(3). Epub 2020 Mar 14.

Candiolo Cancer Institute, FPO-IRCCS, Candiolo 10060 (TO), Italy.

The long-term efficacy of the Epidermal Growth Factor Receptor (EGFR)-targeted antibody cetuximab in advanced colorectal cancer (CRC) patients is limited by the emergence of drug-resistant (persister) cells. Recent studies in other cancer types have shown that cells surviving initial treatment with targeted agents are often vulnerable to alterations in cell metabolism including oxidative stress. Vitamin C (VitC) is an antioxidant agent which can paradoxically trigger oxidative stress at pharmacological dose. Here we tested the hypothesis that VitC in combination with cetuximab could restrain the emergence of secondary resistance to EGFR blockade in CRC wild-type models. We found that addition of VitC to cetuximab impairs the emergence of drug persisters, limits the growth of CRC organoids, and significantly delays acquired resistance in CRC patient-derived xenografts. Mechanistically, proteomic and metabolic flux analysis shows that cetuximab blunts carbohydrate metabolism by blocking glucose uptake and glycolysis, beyond promoting slow but progressive ROS production. In parallel, VitC disrupts iron homeostasis and further increases ROS levels ultimately leading to ferroptosis. Combination of VitC and cetuximab orchestrates a synthetic lethal metabolic cell death program triggered by ATP depletion and oxidative stress, which effectively limits the emergence of acquired resistance to anti-EGFR antibodies. Considering that high-dose VitC is known to be safe in cancer patients, our findings might have clinical impact on CRC patients treated with anti-EGFR therapies.
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http://dx.doi.org/10.3390/cancers12030685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140052PMC
March 2020

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions.

Int J Mol Sci 2020 Mar 6;21(5). Epub 2020 Mar 6.

Department of Medical Sciences, University of Turin, via Nizza, 52, 10126 Torino, Italy.

Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8 cytotoxic and CD4 activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell-cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications.
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http://dx.doi.org/10.3390/ijms21051825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084946PMC
March 2020

HLA typing in lung transplantation: does high resolution fit all?

Ann Transl Med 2020 Feb;8(3):45

AOU Città della Salute e della Scienza University Hospital, Turin, Italy.

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http://dx.doi.org/10.21037/atm.2020.01.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036624PMC
February 2020

A nicotinamide phosphoribosyltransferase-GAPDH interaction sustains the stress-induced NMN/NAD salvage pathway in the nucleus.

J Biol Chem 2020 03 27;295(11):3635-3651. Epub 2020 Jan 27.

Department of Pharmaceutical Sciences, University of Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy. Electronic address:

All cells require sustained intracellular energy flux, which is driven by redox chemistry at the subcellular level. NAD, its phosphorylated variant NAD(P), and its reduced forms NAD(P)/NAD(P)H are all redox cofactors with key roles in energy metabolism and are substrates for several NAD-consuming enzymes ( poly(ADP-ribose) polymerases, sirtuins, and others). The nicotinamide salvage pathway, constituted by nicotinamide mononucleotide adenylyltransferase (NMNAT) and nicotinamide phosphoribosyltransferase (NAMPT), mainly replenishes NAD in eukaryotes. However, unlike NMNAT1, NAMPT is not known to be a nuclear protein, prompting the question of how the nuclear NAD pool is maintained and how it is replenished upon NAD consumption. In the present work, using human and murine cells; immunoprecipitation, pulldown, and surface plasmon resonance assays; and immunofluorescence, small-angle X-ray scattering, and MS-based analyses, we report that GAPDH and NAMPT form a stable complex that is essential for nuclear translocation of NAMPT. This translocation furnishes NMN to replenish NAD to compensate for the activation of NAD-consuming enzymes by stressful stimuli induced by exposure to HO or -nitrosoglutathione and DNA damage inducers. These results indicate that by forming a complex with GAPDH, NAMPT can translocate to the nucleus and thereby sustain the stress-induced NMN/NAD salvage pathway.
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http://dx.doi.org/10.1074/jbc.RA119.010571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076215PMC
March 2020

Genome-Wide Study Updates in the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN).

Front Genet 2019 15;10:1084. Epub 2019 Nov 15.

Division of Transplantation Department of Surgery, University of Pennsylvania, Philadelphia, PA, United States.

The prevalence of end-stage renal disease (ESRD) and the number of kidney transplants performed continues to rise every year, straining the procurement of deceased and living kidney allografts and health systems. Genome-wide genotyping and sequencing of diseased populations have uncovered genetic contributors in substantial proportions of ESRD patients. A number of these discoveries are beginning to be utilized in risk stratification and clinical management of patients. Specifically, genetics can provide insight into the primary cause of chronic kidney disease (CKD), the risk of progression to ESRD, and post-transplant outcomes, including various forms of allograft rejection. The International Genetics & Translational Research in Transplantation Network (iGeneTRAiN), is a multi-site consortium that encompasses >45 genetic studies with genome-wide genotyping from over 51,000 transplant samples, including genome-wide data from >30 kidney transplant cohorts (n = 28,015). iGeneTRAiN is statistically powered to capture both rare and common genetic contributions to ESRD and post-transplant outcomes. The primary cause of ESRD is often difficult to ascertain, especially where formal biopsy diagnosis is not performed, and is unavailable in ∼2% to >20% of kidney transplant recipients in iGeneTRAiN studies. We overview our current copy number variant (CNV) screening approaches from genome-wide genotyping datasets in iGeneTRAiN, in attempts to discover and validate genetic contributors to CKD and ESRD. Greater aggregation and analyses of well phenotyped patients with genome-wide datasets will undoubtedly yield insights into the underlying pathophysiological mechanisms of CKD, leading the way to improved diagnostic precision in nephrology.
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http://dx.doi.org/10.3389/fgene.2019.01084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873800PMC
November 2019

Ectonucleotidases in Blood Malignancies: A Tale of Surface Markers and Therapeutic Targets.

Front Immunol 2019 4;10:2301. Epub 2019 Oct 4.

Department of Medical Sciences, University of Turin, Turin, Italy.

Leukemia develops as the result of intrinsic features of the transformed cell, such as gene mutations and derived oncogenic signaling, and extrinsic factors, such as a tumor-friendly, immunosuppressed microenvironment, predominantly in the lymph nodes and the bone marrow. There, high extracellular levels of nucleotides, mainly NAD and ATP, are catabolized by different ectonucleotidases, which can be divided in two families according to substrate specificity: on one side those that metabolize NAD, including CD38, CD157, and CD203a; on the other, those that convert ATP, namely CD39 (and other ENTPDases) and CD73. They generate products that modulate intracellular calcium levels and that activate purinergic receptors. They can also converge on adenosine generation with profound effects, both on leukemic cells, enhancing chemoresistance and homing, and on non-malignant immune cells, polarizing them toward tolerance. This review will first provide an overview of ectonucleotidases expression within the immune system, in physiological and pathological conditions. We will then focus on different hematological malignancies, discussing their role as disease markers and possibly pathogenic agents. Lastly, we will describe current efforts aimed at therapeutic targeting of this family of enzymes.
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http://dx.doi.org/10.3389/fimmu.2019.02301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788384PMC
November 2020

HaTSPiL: A modular pipeline for high-throughput sequencing data analysis.

PLoS One 2019 15;14(10):e0222512. Epub 2019 Oct 15.

Department of Life Sciences and System Biology, University of Turin, Turin, Italy.

Background: Next generation sequencing methods are widely adopted for a large amount of scientific purposes, from pure research to health-related studies. The decreasing costs per analysis led to big amounts of generated data and to the subsequent improvement of software for the respective analyses. As a consequence, many approaches have been developed to chain different software in order to obtain reliable and reproducible workflows. However, the large range of applications for NGS approaches entails the challenge to manage many different workflows without losing reliability.

Methods: We here present a high-throughput sequencing pipeline (HaTSPiL), a Python-powered CLI tool designed to handle different approaches for data analysis with a high level of reliability. The software relies on the barcoding of filenames using a human readable naming convention that contains any information regarding the sample needed by the software to automatically choose different workflows and parameters. HaTSPiL is highly modular and customisable, allowing the users to extend its features for any specific need.

Conclusions: HaTSPiL is licensed as Free Software under the MIT license and it is available at https://github.com/dodomorandi/hatspil.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222512PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6793853PMC
March 2020

Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation.

Nat Commun 2019 09 11;10(1):4116. Epub 2019 Sep 11.

Department of Medical Sciences, University of Turin, Turin, Italy.

Damage-associated molecular patterns (DAMPs) are molecules that can be actively or passively released by injured tissues and that activate the immune system. Here we show that nicotinate phosphoribosyltransferase (NAPRT), detected by antibody-mediated assays and mass spectrometry, is an extracellular ligand for Toll-like receptor 4 (TLR4) and a critical mediator of inflammation, acting as a DAMP. Exposure of human and mouse macrophages to NAPRT activates the inflammasome and NF-κB for secretion of inflammatory cytokines. Furthermore, NAPRT enhances monocyte differentiation into macrophages by inducing macrophage colony-stimulating factor. These NAPRT-induced effects are independent of NAD-biosynthetic activity, but rely on NAPRT binding to TLR4. In line with our finding that NAPRT mediates endotoxin tolerance in vitro and in vivo, sera from patients with sepsis contain the highest levels of NAPRT, compared to patients with other chronic inflammatory conditions. Together, these data identify NAPRT as a endogenous ligand for TLR4 and a mediator of inflammation.
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http://dx.doi.org/10.1038/s41467-019-12055-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739309PMC
September 2019

Bidirectional linkage between the B-cell receptor and NOTCH1 in chronic lymphocytic leukemia and in Richter's syndrome: therapeutic implications.

Leukemia 2020 02 29;34(2):462-477. Epub 2019 Aug 29.

Department of Medical Sciences, University of Turin, Turin, Italy.

NOTCH1 mutations in chronic lymphocytic leukemia (CLL) lead to accumulation of NOTCH1 intracellular domain (NICD) and prolong signaling. These mutations associate with a more aggressive disease compared to wild-type (WT) CLL. In this work we demonstrate a bidirectional functional relationship between NOTCH1 and the B cell receptor (BCR) pathways. By using highly homogeneous cohorts of primary CLL cells, activation of NOTCH1 is shown to increase expression of surface IgM, as well as LYN, BTK, and BLNK, ultimately enhancing BCR signaling responses, including global mRNA translation. Upon BCR cross-linking, NOTCH1 itself is actively translated and increased on cell surface. Furthermore, BCR ligation induces calcium mobilization that can facilitate ligand-independent NOTCH1 activation. These data suggest that the two pathways are functionally linked, providing a rationale for dual inhibition strategies. Consistently, addition of the γ-secretase inhibitor DAPT to ibrutinib significantly potentiates its effects, both in vitro and in a short-term patient-derived xenograft model. While this observation may find limited applications in the CLL field, it is more relevant for Richter's Syndrome (RS) management, where very few successful therapeutic options exist. Treatment of RS-patient-derived xenografts (RS-PDX) with the combination of ibrutinib and DAPT decreases disease burden and increases overall survival.
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http://dx.doi.org/10.1038/s41375-019-0571-0DOI Listing
February 2020

Subcellular Characterization of Nicotinamide Adenine Dinucleotide Biosynthesis in Metastatic Melanoma by Using Organelle-Specific Biosensors.

Antioxid Redox Signal 2019 11;31(15):1150-1165

Department of Medical Sciences, University of Turin, Turin, Italy.

Nicotinamide adenine dinucleotide (NAD) plays central roles in a wide array of normal and pathological conditions. Inhibition of NAD biosynthesis can be exploited therapeutically in cancer, including melanoma. To obtain quantitation of NAD levels in live cells and to address the issue of the compartmentalization of NAD biosynthesis, we exploited a recently described genetically encoded NAD biosensor (LigA-circularly permutated Venus), which was targeted to the cytosol, mitochondria, and nuclei of A375 melanoma cells, a model of metastatic melanoma (MM). FK866, a specific inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), the main NAD-producing enzyme in MM cells, was used to monitor NAD depletion kinetics at the subcellular level in biosensor-transduced A375 cells. In addition, we treated FK866-blocked A375 cells with NAD precursors, including nicotinamide, nicotinic acid, nicotinamide riboside, and quinolinic acid, highlighting an organelle-specific capacity of each substrate to rescue from NAMPT block. Expression of NAD biosynthetic enzymes was then biochemically studied in isolated organelles, revealing the presence of NAMPT in all three cellular compartments, whereas nicotinate phosphoribosyltransferase was predominantly cytosolic and mitochondrial, and nicotinamide riboside kinase mitochondrial and nuclear. In keeping with biosensor data, quinolinate phosphoribosyltransferase was expressed at extremely low levels. Throughout this work, we validated the use of genetically encoded NAD biosensors to characterize subcellular distribution of NAD production routes in MM. The chance of real-time monitoring of NAD fluctuations after chemical perturbations, together with a deeper comprehension of the cofactor biosynthesis compartmentalization, strengthens the foundation for a targeted strategy of NAD pool manipulation in cancer and metabolic diseases.
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http://dx.doi.org/10.1089/ars.2019.7799DOI Listing
November 2019

NAD-Biosynthetic and Consuming Enzymes as Central Players of Metabolic Regulation of Innate and Adaptive Immune Responses in Cancer.

Front Immunol 2019 25;10:1720. Epub 2019 Jul 25.

Department of Medical Sciences, University of Turin, Turin, Italy.

Cancer cells, particularly in solid tumors, are surrounded by non-neoplastic elements, including endothelial and stromal cells, as well as cells of immune origin, which can support tumor growth by providing the right conditions. On the other hand, local hypoxia, and lack of nutrients induce tumor cells to reprogram their metabolism in order to survive, proliferate, and disseminate: the same conditions are also responsible for building a tumor-suppressive microenvironment. In addition to tumor cells, it is now well-recognized that metabolic rewiring occurs in all cellular components of the tumor microenvironment, affecting epigenetic regulation of gene expression and influencing differentiation/proliferation decisions of these cells. Nicotinamide adenine dinucleotide (NAD) is an essential co-factor for energy transduction in metabolic processes. It is also a key component of signaling pathways, through the regulation of NAD-consuming enzymes, including sirtuins and PARPs, which can affect DNA plasticity and accessibility. In addition, both NAD-biosynthetic and NAD-consuming enzymes can be present in the extracellular environment, adding a new layer of complexity to the system. In this review we will discuss the role of the "NADome" in the metabolic cross-talk between cancer and infiltrating immune cells, contributing to cancer growth and immune evasion, with an eye to therapeutic implications.
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http://dx.doi.org/10.3389/fimmu.2019.01720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671870PMC
October 2020
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