Old and new faces of neutropenia in children

Dufour, Carlo; Miano, Maurizio; Fioredda, Francesca

doi:10.3324/haematol.2016.142760

Cited by 19 publications

(9 citation statements)

References 40 publications

(47 reference statements)

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“…Because most patients with SCN and CyN are now treated with G-CSF to prevent severe infections, it is not possible to determine precisely the contribution of G-CSF, if any, to the risk of AML. However, concerns persist, and experts recommend that longterm treatment with G-CSF should be administered conservatively and only to patients with recurrent fever and infections [29][30][31]. In addition, G-CSF must be administered s.c., usually daily or every other day, presumably for the entire life of the patient.…”

Section: Discussionmentioning

confidence: 99%

Elastase inhibitors as potential therapies for ELANE-associated neutropenia

Makaryan

Kelley

Fletcher

et al. 2017

Journal of Leukocyte Biology

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Mutations in , the gene for neutrophil elastase (NE), a protease expressed early in neutrophil development, are the most frequent cause of cyclic (CyN) and severe congenital neutropenia (SCN). We hypothesized that inhibitors of NE, acting either by directly inhibiting enzymatic activity or as chaperones for the mutant protein, might be effective as therapy for CyN and SCN. We investigated β-lactam-based inhibitors of human NE (Merck Research Laboratories, Kenilworth, NJ, USA), focusing on 1 inhibitor called MK0339, a potent, orally absorbed agent that had been tested in clinical trials and shown to have a favorable safety profile. Because fresh, primary bone marrow cells are rarely available in sufficient quantities for research studies, we used 3 cellular models: patient-derived, induced pluripotent stem cells (iPSCs); HL60 cells transiently expressing mutant NE; and HL60 cells with regulated expression of the mutant enzyme. In all 3 models, the cells expressing the mutant enzyme had reduced survival as measured with annexin V and FACS. Coincubation with the inhibitors, particularly MK0339, promoted cell survival and increased formation of mature neutrophils. These studies suggest that cell-permeable inhibitors of neutrophil elastase show promise as novel therapies for-associated neutropenia.

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Section: Discussionmentioning

confidence: 99%

Elastase inhibitors as potential therapies for ELANE-associated neutropenia

Makaryan

Kelley

Fletcher

et al. 2017

Journal of Leukocyte Biology

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“…13 Some of these mutations are present in both SCN and CyN patients, but some are restricted to SCN patients without a clear explanation of how a given genetic lesion may be associated with different phenotypes. 14 Interestingly, mice carrying mutations in Elane did not show an effect in murine granulopoiesis, unless challenged by bortezomib. 15–17 …”

Section: Monogenic Disorders and Syndromesmentioning

confidence: 99%

“…14 The molecular mechanisms by which ELANE mutations disrupt granulopoiesis is not well understood. A number of studies have demonstrated that ELANE mutations result in neutrophil elastase protein misfolding, induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and ultimately a block in granulocytic differentiation.…”

Section: Monogenic Disorders and Syndromesmentioning

confidence: 99%

New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing

Corey

Oyarbide

2017

Hematology

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Neutrophils are the most common type of leukocyte in human circulating blood and constitute one of the chief mediators for innate immunity. Defined as a reduction from a normal distribution of values, neutropenia results from a number of congenital and acquired conditions. Neutropenia may be insignificant, temporary, or associated with a chronic condition with or without a vulnerability to life-threatening infections. As an inherited bone marrow failure syndrome, neutropenia may be associated with transformation to myeloid malignancy. Recognition of an inherited bone marrow failure syndrome may be delayed into adulthood. The list of monogenic neutropenia disorders is growing, heterogeneous, and bewildering. Furthermore, greater knowledge of immune-mediated and drug-related causes makes the diagnosis and management of neutropenia challenging. Recognition of syndromic presentations and especially the introduction of next-generation sequencing are improving the accuracy and expediency of diagnosis as well as their clinical management. Furthermore, identification of monogenic neutropenia disorders is shedding light on the molecular mechanisms of granulopoiesis and myeloid malignancies.

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“…Neutropenia generally presents in the first year of life (range 2–54 months), and resolves by age 2–4 years. 8–10 This form of neutropenia, the “most common” form of chronic neutropenia in childhood, is quite rare, occurring in only about 1/100,000 children per year; 11 however, many cases are probably undetected, as the asymptomatic children have no clinical indications for blood counts.…”

Section: Chronic Neutropeniamentioning

confidence: 99%

Autoimmune and other acquired neutropenias

Newburger

2016

Hematology

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This educational review addresses the diagnostic evaluation of patients for autoimmune and other forms of acquired neutropenia, including the futility of deconstructing the overlap of chronic “autoimmune,” “benign,” and “idiopathic” categories. Isolated neutropenias due to infection, drugs, and immunological disorders are also addressed. Discussion of management options emphasizes a conservative approach with largely supportive care for these mostly benign and self-limited disorders.

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Old and new faces of neutropenia in children

Cited by 19 publications

References 40 publications

Elastase inhibitors as potential therapies for ELANE-associated neutropenia

Elastase inhibitors as potential therapies for ELANE-associated neutropenia

New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing

Autoimmune and other acquired neutropenias

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