Granulopoiesis and granules of human neutrophils

Cowland, Jack B.; Borregaard, Niels

doi:10.1111/imr.12440

Cited by 310 publications

(393 citation statements)

References 193 publications

(254 reference statements)

Supporting

Mentioning

384

Contrasting

Unclassified

Order By: Relevance

“…Following culture in the presence of 5 μmol/L AG-221 for 8 days, IDH2 R140Q blast cells (AML-8) exhibited granules colocalizing with lactoferrin ( Fig. 2E), a canonical marker of secondary and tertiary granules (35), and a significantly higher number of cells with multilobed nuclei compared with control (mean ± SEM 32.4% ± 3.3% vs. 10.6% ± 1.8%; P < 0.001 by Student t test; Fig. 2F).…”

Section: Ag-221 Stabilizes the Inhibitory Open Homodimer Conformationmentioning

confidence: 99%

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

et al. 2017

View full text Add to dashboard Cite

Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2 R140Q -mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies. SIGNIFICANCE:Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478-93.

show abstract

Section: Ag-221 Stabilizes the Inhibitory Open Homodimer Conformationmentioning

confidence: 99%

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Secondary (specific) granules are large stores for soluble mediators as well as for NADPH oxidase that supports oxidative burst. The tertiary granules and secretory vesicles support migration and interaction of neutrophils with the environment (96). …”

Section: Regulation Of Oxidative Burst By Type I Ifnsmentioning

confidence: 99%

The Essential Role of Type I Interferons in Differentiation and Activation of Tumor-Associated Neutrophils

2016

View full text Add to dashboard Cite

Type I interferons (IFNs) were first characterized in the process of viral interference. However, since then, IFNs are found to be involved in a wide range of biological processes. In the mouse, type I IFNs comprise a large family of cytokines. At least 12 IFN-α and one IFN-β can be found and they all signal through the same receptor (IFNAR). A hierarchy of expression has been established for type I IFNs, where IFN-β is induced first and it activates in a paracrine and autocrine fashion a cascade of other type I IFNs. Besides its importance in the induction of the IFN cascade, IFN-β is also constitutively expressed in low amounts under normal non-inflammatory conditions, thus facilitating “primed” state of the immune system. In the context of cancer, type I IFNs show strong antitumor function as they play a key role in mounting antitumor immune responses through the modulation of neutrophil differentiation, activation, and migration. Owing to their plasticity, neutrophils play diverse roles during cancer development and metastasis since they possess both tumor-promoting (N2) and tumor-limiting (N1) properties. Notably, the differentiation into antitumor phenotype is strongly supported by type I IFNs. It could also be shown that these cytokines are critical for the suppression of neutrophil migration into tumor and metastasis site by regulating chemokine receptors, e.g., CXCR2 on these cells and by influencing their longevity. Type I IFNs limit the life span of neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Such antitumor neutrophils efficiently suppress the pro-angiogenic factors expression, e.g., vascular endothelial growth factor and matrix metallopeptidase 9. This in turn restricts tumor vascularization and growth. Thus, type I IFNs appear to be the part of the natural tumor surveillance mechanism. Here we provide an up to date review of how type I IFNs influence the pro- and antitumor properties of neutrophils. Understanding these mechanisms is particularly important from a therapeutic point of view.

show abstract

“…Phagosomes containing P. aeruginosa fuse intracellularly with PMN granules storing an arsenal of antimicrobial molecules (detailed in [106]). The phagolysosome fusion creates a special, confined niche in which bacteria can be eliminated efficiently in a precise surgical way without significant leaking of the dangerous PMN cargo into the environment [100].…”

Section: Antimicrobial Mechanisms Of Neutrophils Against Pseudomonmentioning

confidence: 99%

“…The phagolysosome fusion creates a special, confined niche in which bacteria can be eliminated efficiently in a precise surgical way without significant leaking of the dangerous PMN cargo into the environment [100]. Four types of PMN granules have been categorized and referred to as primary (or azurophil), secondary (or specific), tertiary (or gelatinase) granules and secretory vesicles [106]. Secretory vesicles are membrane vesicles derived from the plasma membrane primarily containing plasma membrane proteins and extracellular milieu [106].…”

Section: Antimicrobial Mechanisms Of Neutrophils Against Pseudomonmentioning

confidence: 99%

“…Four types of PMN granules have been categorized and referred to as primary (or azurophil), secondary (or specific), tertiary (or gelatinase) granules and secretory vesicles [106]. Secretory vesicles are membrane vesicles derived from the plasma membrane primarily containing plasma membrane proteins and extracellular milieu [106]. Primary, secondary and tertiary granules have specific contents and fuse with the phagosome in a reverse order, tertiary granules first and primary granules last [106].…”

Section: Antimicrobial Mechanisms Of Neutrophils Against Pseudomonmentioning

confidence: 99%

See 1 more Smart Citation

Interactions between Neutrophils and Pseudomonas aeruginosa in Cystic Fibrosis

Rada

2017

Pathogens

102

View full text Add to dashboard Cite

Cystic fibrosis (CF) affects 70,000 patients worldwide. Morbidity and mortality in CF is largely caused by lung complications due to the triad of impaired mucociliary clearance, microbial infections and chronic inflammation. Cystic fibrosis airway inflammation is mediated by robust infiltration of polymorphonuclear neutrophil granulocytes (PMNs, neutrophils). Neutrophils are not capable of clearing lung infections and contribute to tissue damage by releasing their dangerous cargo. Pseudomonas aeruginosa is an opportunistic pathogen causing infections in immunocompromised individuals. P. aeruginosa is a main respiratory pathogen in CF infecting most patients. Although PMNs are key to attack and clear P. aeruginosa in immunocompetent individuals, PMNs fail to do so in CF. Understanding why neutrophils cannot clear P. aeruginosa in CF is essential to design novel therapies. This review provides an overview of the antimicrobial mechanisms by which PMNs attack and eliminate P. aeruginosa. It also summarizes current advances in our understanding of why PMNs are incapable of clearing P. aeruginosa and how this bacterium adapts to and resists PMN-mediated killing in the airways of CF patients chronically infected with P. aeruginosa.

show abstract

Granulopoiesis and granules of human neutrophils

Cited by 310 publications

References 193 publications

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

The Essential Role of Type I Interferons in Differentiation and Activation of Tumor-Associated Neutrophils

Interactions between Neutrophils and Pseudomonas aeruginosa in Cystic Fibrosis

Contact Info

Product

Resources

About