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Article ; Online: Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons.

Santhosh Kumar, Saranya / Naseri, Nima N / Pather, Sarshan R / Hallacli, Erinc / Ndayisaba, Alain / Buenaventura, Chris / Acosta, Karen / Roof, Jennifer / Fazelinia, Hossein / Spruce, Lynn A / Luk, Kelvin / Khurana, Vikram / Rhoades, Elizabeth / Shalem, Ophir

Science advances

2024 Volume 10, Issue 6, Page(s) eadj4767

Abstract: Alpha-synuclein (αSyn) protein levels correlate with the risk and severity of Parkinson's disease and related neurodegenerative diseases. Lowering αSyn is being actively investigated as a therapeutic modality. Here, we systematically map the regulatory ... ...

Abstract	Alpha-synuclein (αSyn) protein levels correlate with the risk and severity of Parkinson's disease and related neurodegenerative diseases. Lowering αSyn is being actively investigated as a therapeutic modality. Here, we systematically map the regulatory network that controls endogenous αSyn using sequential CRISPR-knockout and -interference screens in an αSyn gene (
MeSH term(s)	Humans ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism ; Cell Line ; Clustered Regularly Interspaced Short Palindromic Repeats ; Neurons/metabolism ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; N-Terminal Acetyltransferase B/antagonists & inhibitors ; N-Terminal Acetyltransferase B/metabolism ; Methionyl Aminopeptidases/antagonists & inhibitors ; Methionyl Aminopeptidases/metabolism
Chemical Substances	alpha-Synuclein ; NAA20 protein, human (EC 2.3.1.254) ; N-Terminal Acetyltransferase B (EC 2.3.1.255) ; METAP2 protein, human (EC 3.4.11.18) ; Methionyl Aminopeptidases (EC 3.4.11.18)
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adj4767
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Article ; Online: Urine Proteomics: Evaluation of Different Sample Preparation Workflows for Quantitative, Reproducible, and Improved Depth of Analysis.

Ding, Hua / Fazelinia, Hossein / Spruce, Lynn A / Weiss, Dana A / Zderic, Stephen A / Seeholzer, Steven H

Journal of proteome research

2020 Volume 19, Issue 4, Page(s) 1857–1862

Abstract: The growing field of urinary proteomics shows promise to expand the number of biomarkers for the diagnosis and prognosis of a number of human diseases. With the rapid developments in mass spectrometry methods for proteome quantification, there exists an ... ...

Abstract	The growing field of urinary proteomics shows promise to expand the number of biomarkers for the diagnosis and prognosis of a number of human diseases. With the rapid developments in mass spectrometry methods for proteome quantification, there exists an opportunity for improved sample processing and separation workflows to make important contributions to urine proteomic analyses. Here we evaluate the performance of four sample preparation methods: MStern, PreOmics in-StageTip (iST), suspension-trapping (S-Trap), and conventional urea In-Solution trypsin hydrolysis for nondepleted urine samples. Data-dependent acquisition (DDA) mode on a QExactive HF mass spectrometer was used for single-shot label-free data acquisition. Our results demonstrate a high degree of reproducibility within each workflow. PreOmics iST yields the best digestion efficiency, whereas the S-Trap workflow gives the greatest number of peptide and protein identifications. Using the S-Trap method and starting with ∼0.5 mL, we identify ∼1500 protein groups and ∼17 700 peptides from DDA analysis with a single injection on the mass spectrometer.
MeSH term(s)	Humans ; Mass Spectrometry ; Proteome ; Proteomics ; Reproducibility of Results ; Specimen Handling ; Workflow
Chemical Substances	Proteome
Language	English
Publishing date	2020-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.9b00772
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Article: Phosphoproteomics reveals content and signaling differences between neonatal and adult platelets.

Thom, Christopher S / Davenport, Patricia / Fazelinia, Hossein / Liu, Zhi-Jian / Zhang, Haorui / Ding, Hua / Roof, Jennifer / Spruce, Lynn A / Ischiropoulos, Harry / Sola-Visner, Martha

bioRxiv : the preprint server for biology

2023

Abstract: Background and objective: Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests ... ...

Abstract	Background and objective: Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental differences in platelet immune functions. This study was designed to compare the proteome and phosphoproteome of resting adult and neonatal platelets. Methods: We isolated resting umbilical cord blood-derived platelets from healthy full term neonates (n=9) and resting blood platelets from healthy adults (n=7), and compared protein and phosphoprotein contents using data independent acquisition mass spectrometry. Results: We identified 4745 platelet proteins with high confidence across all samples. Adult and neonatal platelets clustered separately by principal component analysis. Adult platelets were significantly enriched for immunomodulatory proteins, including β2 microglobulin and CXCL12, whereas neonatal platelets were enriched for ribosomal components and proteins involved in metabolic activities. Adult platelets were enriched for phosphorylated GTPase regulatory enzymes and proteins participating in trafficking, which may help prime them for activation and degranulation. Neonatal platelets were enriched for phosphorylated proteins involved in insulin growth factor signaling. Conclusions: Using state-of-the-art mass spectrometry, our findings expanded the known neonatal platelet proteome and identified important differences in protein content and phosphorylation compared with adult platelets. These developmental differences suggested enhanced immune functions for adult platelets and presence of a molecular machinery related to platelet activation. These findings are important to understanding mechanisms underlying key platelet functions as well as the harmful effects of adult platelet transfusions given to preterm infants.
Language	English
Publishing date	2023-09-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.13.557268
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Article ; Online: Quantitative label-free mass spectrometry reveals content and signaling differences between neonatal and adult platelets.

Thom, Christopher S / Davenport, Patricia / Fazelinia, Hossein / Soule-Albridge, Erin / Liu, Zhi-Jian / Zhang, Haorui / Feldman, Henry A / Ding, Hua / Roof, Jennifer / Spruce, Lynn A / Ischiropoulos, Harry / Sola-Visner, Martha

Journal of thrombosis and haemostasis : JTH

2023 Volume 22, Issue 5, Page(s) 1447–1462

Abstract: Background: Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental ... ...

Abstract	Background: Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental differences in platelet immune functions. Objectives: This study was designed to compare the proteome and phosphoproteome of resting adult and neonatal platelets. Methods: We isolated resting umbilical cord blood-derived platelets from healthy full-term neonates (n = 8) and resting blood platelets from healthy adults (n = 6) and compared protein and phosphoprotein contents using data-independent acquisition mass spectrometry. Results: We identified 4770 platelet proteins with high confidence across all samples. Adult and neonatal platelets were clustered separately by principal component analysis. Adult platelets were significantly enriched in immunomodulatory proteins, including β2 microglobulin and CXCL12, whereas neonatal platelets were enriched in ribosomal components and proteins involved in metabolic activities. Adult platelets were enriched in phosphorylated GTPase regulatory enzymes and proteins participating in trafficking, which may help prime them for activation and degranulation. Neonatal platelets were enriched in phosphorylated proteins involved in insulin growth factor signaling. Conclusion: Using label-free data-independent acquisition mass spectrometry, our findings expanded the known neonatal platelet proteome and identified important differences in protein content and phosphorylation between neonatal and adult platelets. These developmental differences suggested enhanced immune functions for adult platelets and presence of molecular machinery related to platelet activation. These findings are important to understanding mechanisms underlying key platelet functions as well as the harmful effects of adult platelet transfusions given to preterm infants.
MeSH term(s)	Humans ; Blood Platelets/metabolism ; Infant, Newborn ; Signal Transduction ; Adult ; Fetal Blood/metabolism ; Fetal Blood/cytology ; Phosphorylation ; Proteomics/methods ; Phosphoproteins/blood ; Proteome ; Female ; Age Factors ; Male ; Principal Component Analysis ; Mass Spectrometry ; Tandem Mass Spectrometry
Chemical Substances	Phosphoproteins ; Proteome
Language	English
Publishing date	2023-12-30
Publishing country	England
Document type	Journal Article ; Comparative Study ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2023.12.022
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Zs.A 5805: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Neutral sphingomyelinase blockade enhances hematopoietic stem cell fitness through an integrated stress response.

Hurwitz, Stephanie N / Jung, Seul K / Kobulsky, Danielle R / Fazelinia, Hossein / Spruce, Lynn A / Pérez, Empar Baltasar / Groen, Nathalie / Mesaros, Clementina / Kurre, Peter

Blood

2023 Volume 142, Issue 20, Page(s) 1708–1723

Abstract: Hematopoietic stem and progenitor cell (HSPC) transplantation serves as a curative therapy for many benign and malignant hematopoietic disorders and as a platform for gene therapy. However, growing needs for ex vivo manipulation of HSPC-graft products ... ...

Abstract	Hematopoietic stem and progenitor cell (HSPC) transplantation serves as a curative therapy for many benign and malignant hematopoietic disorders and as a platform for gene therapy. However, growing needs for ex vivo manipulation of HSPC-graft products are limited by barriers in maintaining critical self-renewal and quiescence properties. The role of sphingolipid metabolism in safeguarding these essential cellular properties has been recently recognized, but not yet widely explored. Here, we demonstrate that pharmacologic and genetic inhibition of neutral sphingomyelinase 2 (nSMase-2) leads to sustained improvements in long-term competitive transplantation efficiency after ex vivo culture. Mechanistically, nSMase-2 blockade activates a canonical integrated stress response (ISR) and promotes metabolic quiescence in human and murine HSPCs. These adaptations result in part from disruption in sphingolipid metabolism that impairs the release of nSMase-2-dependent extracellular vesicles (EVs). The aggregate findings link EV trafficking and the ISR as a regulatory dyad guarding HSPC homeostasis and long-term fitness. Translationally, transient nSMase-2 inhibition enables ex vivo graft manipulation with enhanced HSPC potency.
MeSH term(s)	Animals ; Humans ; Mice ; Sphingomyelin Phosphodiesterase/genetics ; Sphingomyelin Phosphodiesterase/metabolism ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cell Transplantation ; Sphingolipids/metabolism
Chemical Substances	Sphingomyelin Phosphodiesterase (EC 3.1.4.12) ; Sphingolipids
Language	English
Publishing date	2023-09-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023022147
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Zs.MO 364: Show issues

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Article ; Online: Proteomics identifies novel biomarkers of synovial joint disease in a canine model of mucopolysaccharidosis I.

Zhang, Chenghao / Gawri, Rahul / Lau, Yian Khai / Spruce, Lynn A / Fazelinia, Hossein / Jiang, Zhirui / Jo, Stephanie Y / Scanzello, Carla R / Mai, Wilfried / Dodge, George R / Casal, Margret L / Smith, Lachlan J

Molecular genetics and metabolism

2023 Volume 138, Issue 2, Page(s) 107371

Abstract: Mucopolysaccharidosis I is a lysosomal storage disorder characterized by deficient alpha-L-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans in cells and tissues. Synovial joint disease is prevalent and significantly reduces ... ...

Abstract	Mucopolysaccharidosis I is a lysosomal storage disorder characterized by deficient alpha-L-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a critical need for improved understanding of joint disease pathophysiology in MPS I, including specific biomarkers to predict and monitor joint disease progression, and response to treatment. The objective of this study was to leverage the naturally-occurring MPS I canine model and undertake an unbiased proteomic screen to identify systemic biomarkers predictive of local joint disease in MPS I. Synovial fluid and serum samples were collected from MPS I and healthy dogs at 12 months-of-age, and protein abundance characterized using liquid chromatography tandem mass spectrometry. Stifle joints were evaluated postmortem using magnetic resonance imaging (MRI) and histology. Proteomics identified 40 proteins for which abundance was significantly correlated between serum and synovial fluid, including markers of inflammatory joint disease and lysosomal dysfunction. Elevated expression of three biomarker candidates, matrix metalloproteinase 19, inter-alpha-trypsin inhibitor heavy-chain 3 and alpha-1-microglobulin, was confirmed in MPS I cartilage, and serum abundance of these molecules was found to correlate with MRI and histological degenerative grades. The candidate biomarkers identified have the potential to improve patient care by facilitating minimally-invasive, specific assessment of joint disease progression and response to therapeutic intervention.
MeSH term(s)	Dogs ; Animals ; Mucopolysaccharidosis I/pathology ; Proteomics ; Quality of Life ; Joint Diseases/metabolism ; Synovial Fluid/metabolism ; Biomarkers/metabolism ; Disease Progression
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2023.107371
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Zs.A 617: Show issues

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Article ; Online: Mitochondrial morphology, bioenergetics and proteomic responses in fatty acid oxidation disorders.

Raimo, Serena / Zura-Miller, Gabriella / Fezelinia, Hossein / Spruce, Lynn A / Zakopoulos, Iordanis / Mohsen, Al-Walid / Vockley, Jerry / Ischiropoulos, Harry

Redox biology

2021 Volume 41, Page(s) 101923

Abstract: Mutations in nuclear genes encoding for mitochondrial proteins very long-chain acyl-CoA dehydrogenase (VLCAD) and trifunctional protein (TFP) cause rare autosomal recessive disorders. Studies in fibroblasts derived from patients with mutations in VLCAD ... ...

Abstract	Mutations in nuclear genes encoding for mitochondrial proteins very long-chain acyl-CoA dehydrogenase (VLCAD) and trifunctional protein (TFP) cause rare autosomal recessive disorders. Studies in fibroblasts derived from patients with mutations in VLCAD and TFP exhibit mitochondrial defects. To gain insights on pathological changes that account for the mitochondrial deficits we performed quantitative proteomic, biochemical, and morphometric analyses in fibroblasts derived from subjects with three different VLCAD and three different TFP mutations. Proteomic data that was corroborated by antibody-based detection, indicated reduced levels of VLCAD and TFP protein in cells with VLCAD and TFP mutations respectively, which in part accounted for the diminished fatty acid oxidation capacity. Decreased mitochondrial respiratory capacity in cells with VLCAD and TFP mutations was quantified after glucose removal and cells with TFP mutations had lower levels of glycogen. Despite these energetic deficiencies, the cells with VLCAD and TFP mutations did not exhibit changes in mitochondria morphology, distribution, fusion and fission, quantified by either confocal or transmission electron microscopy and corroborated by proteomic and antibody-based protein analysis. Fibroblasts with VLCAD and to a lesser extend cells with TFP mutations had increased levels of mitochondrial respiratory chain proteins and proteins that facilitate the assembly of respiratory complexes. With the exception of reduced levels of catalase and glutathione S-transferase theta-1 in cells with TFP mutations, the levels of 45 proteins across all major intracellular antioxidant networks were similar between cells with VLCAD and TFP mutations and non-disease controls. Collectively the data indicate that despite the metabolic deficits, cells with VLCAD and TFP mutations maintain their proteomic integrity to preserve cellular and mitochondria architecture, support energy production and protect against oxidative stress.
MeSH term(s)	Acyl-CoA Dehydrogenase, Long-Chain/metabolism ; Energy Metabolism ; Fatty Acids ; Humans ; Lipid Metabolism, Inborn Errors ; Mitochondria/metabolism ; Proteomics
Chemical Substances	Fatty Acids ; Acyl-CoA Dehydrogenase, Long-Chain (EC 1.3.8.8)
Language	English
Publishing date	2021-03-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2021.101923
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Article ; Online: Plasma Nucleosomes Are Associated With Mortality in Pediatric Acute Respiratory Distress Syndrome.

Yehya, Nadir / Fazelinia, Hossein / Lawrence, Gladys G / Spruce, Lynn A / Mai, Mark V / Worthen, G Scott / Christie, Jason D

Critical care medicine

2021 Volume 49, Issue 7, Page(s) 1149–1158

Abstract: Objectives: Circulating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown.: Design: ...

Abstract	Objectives: Circulating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown. Design: We performed a prospective cohort study in children with acute respiratory distress syndrome, with plasma collection within 24 hours of acute respiratory distress syndrome onset. We associated nucleosome levels with severity of acute respiratory distress syndrome and with nonpulmonary organ failures and tested for association of nucleosomes with PICU mortality and ventilator-free days at 28 days in univariate and multivariable analyses. We also performed proteomics of DNA-bound plasma proteins in a matched case-control study of septic children with and without acute respiratory distress syndrome in order to identify specific histone proteins elevated in acute respiratory distress syndrome. Setting: Large academic tertiary-care PICU. Patients: Intubated children meeting Berlin criteria for acute respiratory distress syndrome. Interventions: None. Measurements and main results: We enrolled 333 children with acute respiratory distress syndrome, with 69 nonsurvivors (21%). Plasma nucleosomes were correlated with acute respiratory distress syndrome severity and with the number of nonpulmonary organ failures at acute respiratory distress syndrome onset. Nucleosomes were higher (p < 0.001) in nonsurvivors (0.40 [interquartile range, 0.20-0.71] arbitrary units) relative to survivors (0.10 [interquartile range, 0.04-0.25] arbitrary units). Nucleosomes were associated with PICU mortality in multivariable analysis (adjusted odds ratio 1.84 per 1 sd increase; 95% CI, 1.38-2.45; p < 0.001). Nucleosomes were also associated with a lower probability of being extubated alive by day 28 after multivariable adjustment (adjusted subdistribution hazard ratio, 0.74; 95% CI, 0.63-0.88; p = 0.001). Proteomic analysis demonstrated higher levels of the core nucleosome histones H2A, H2B, H3, and H4 in septic children with acute respiratory distress syndrome, relative to septic children without acute respiratory distress syndrome. Conclusions: Plasma nucleosomes are associated with acute respiratory distress syndrome severity, nonpulmonary organ failures, and worse outcomes in pediatric acute respiratory distress syndrome.
MeSH term(s)	Adolescent ; Airway Extubation ; Case-Control Studies ; Child ; Child, Preschool ; DNA/blood ; Female ; Histones/blood ; Hospital Mortality ; Humans ; Intensive Care Units, Pediatric ; Male ; Multiple Organ Failure/mortality ; Nucleosomes/metabolism ; Prognosis ; Prospective Studies ; Proteomics ; Respiration, Artificial ; Respiratory Distress Syndrome/blood ; Respiratory Distress Syndrome/complications ; Respiratory Distress Syndrome/mortality ; Sepsis/blood ; Sepsis/complications ; Severity of Illness Index ; Survival Rate
Chemical Substances	Histones ; Nucleosomes ; DNA (9007-49-2)
Language	English
Publishing date	2021-04-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	197890-1
ISSN	1530-0293 ; 0090-3493
ISSN (online)	1530-0293
ISSN	0090-3493
DOI	10.1097/CCM.0000000000004923
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Zs.A 1261: Show issues

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Article ; Online: c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8

Dar, Asif A / Kim, Dale D / Gordon, Scott M / Klinzing, Kathleen / Rosen, Siera / Guha, Ipsita / Porter, Nadia / Ortega, Yohaniz / Forsyth, Katherine S / Roof, Jennifer / Fazelinia, Hossein / Spruce, Lynn A / Eisenlohr, Laurence C / Behrens, Edward M / Oliver, Paula M

Nature communications

2023 Volume 14, Issue 1, Page(s) 7098

Abstract: During infection, virus-specific ... ...

Abstract	During infection, virus-specific CD8
MeSH term(s)	CD8-Positive T-Lymphocytes/immunology ; Cell Cycle ; Cullin Proteins/metabolism ; Lymphocytic choriomeningitis virus ; Ubiquitin-Protein Ligases/metabolism ; Proto-Oncogene Proteins c-myc/metabolism
Chemical Substances	Cullin Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2023-11-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-42765-7
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Article ; Online: FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells.

Yang, Scarlett Y / Hayer, Katharina E / Fazelinia, Hossein / Spruce, Lynn A / Asnani, Mukta / Black, Kathryn L / Naqvi, Ammar S / Pillai, Vinodh / Barash, Yoseph / Elenitoba-Johnson, Kojo S J / Thomas-Tikhonenko, Andrei

Blood advances

2022 Volume 7, Issue 7, Page(s) 1077–1091

Abstract: Noncanonical exon usage plays many important roles in cellular phenotypes, but its contribution to human B-cell development remains sketchily understood. To fill this gap, we collected various B-cell fractions from bone marrow (BM) and tonsil donors, ... ...

Abstract	Noncanonical exon usage plays many important roles in cellular phenotypes, but its contribution to human B-cell development remains sketchily understood. To fill this gap, we collected various B-cell fractions from bone marrow (BM) and tonsil donors, performed RNA sequencing, and examined transcript variants. We identified 150 genes that harbor local splicing variations in all pairwise comparisons. One of them encodes FBXW7, an E3 ubiquitin ligase implicated as a driver in several blood cancers. Surprisingly, we discovered that in normal human pro-B cells, the predominant transcript used an alternative first exon to produce the poorly characterized FBXW7β isoform, previously thought to be restricted to neural tissues. The FBXW7β transcript was also abundant in cell lines and primary samples of pediatric B-cell acute lymphoblastic leukemia (B-ALL), which originates in the BM. When overexpressed in a heterologous cell system, this transcript yielded the expected protein product, as judged by anti-FLAG immunoblotting and mass spectrometry. Furthermore, in REH B-ALL cells, FBXW7β mRNA was the only FBXW7 isoform enriched in the polyribosome fraction. To shed light on possible functions of FBXW7β, we used gain- and loss-of-function approaches and identified an FBXW7-dependent inflammatory gene signature, apparent in a subset of B-ALL with high FBXW7β expression. This signature contained several members of the tumor necrosis factor superfamily, including those comprising the HLA Class III cluster (LTB, LST1, NCR3, LTA, and NFKBIL1). Our findings suggest that FBXW7β expression drives proinflammatory responses, which could contribute to normal B-cell development, leukemogenesis, and responses to anticancer therapies.
MeSH term(s)	Child ; Humans ; Cell Line ; F-Box-WD Repeat-Containing Protein 7/genetics ; F-Box-WD Repeat-Containing Protein 7/metabolism ; Precursor Cells, B-Lymphoid/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Transcriptional Activation
Chemical Substances	F-Box-WD Repeat-Containing Protein 7 ; Protein Isoforms
Language	English
Publishing date	2022-11-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022007910
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