Neutrophils are the shortest-lived blood cells, which requires a prodigious degree of proliferation and differentiation to sustain physiologically sufficient numbers and be poised to respond quickly to infectious emergencies. More than 10 neutrophils are produced every minute in an adult bone marrow-a process that is tightly regulated by a small group of cytokines and chemical mediators and dependent on nutrients and energy. Like granulocyte colony-stimulating factor, the primary growth factor for granulopoiesis, they stimulate signalling pathways, some affecting metabolism. Nutrient or energy deficiency stresses the survival, proliferation, and differentiation of neutrophils and their precursors. Thus, it is not surprising that monogenic disorders related to metabolism exist that result in neutropenia. Among these are pathogenic mutations in HAX1, G6PC3, SLC37A4, TAFAZZIN, SBDS, EFL1 and the mitochondrial disorders. These mutations perturb carbohydrate, lipid and/or protein metabolism. We hypothesize that metabolic disturbances may drive the pathogenesis of a subset of inherited neutropenias just as defects in DNA damage response do in Fanconi anaemia, telomere maintenance in dyskeratosis congenita and ribosome formation in Diamond-Blackfan anaemia. Greater understanding of metabolic pathways in granulopoiesis will identify points of vulnerability in production and may point to new strategies for the treatment of neutropenias.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1111/bjh.19192 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Incidental neutropenia: An emergency medicine focused approach.
Am J Emerg Med
December 2024
The University of Texas Southwestern Medical Center, Department of Emergency Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390, United States.
Introduction: Neutropenia is defined as an absolute neutrophil count (ANC) < 1500 cells/microL and may be discovered incidentally in an asymptomatic, afebrile patient.
Objective: This narrative review provides an approach to the afebrile emergency department patient with incidental neutropenia.
Discussion: Neutropenia is an ANC < 1500 cells/microL, with mild neutropenia defined as an ANC ≥ 1000 to <1500 cells/microL, moderate ≥500 to <1000 cells/microL, severe <500 cells/microL, and agranulocytosis <200 cells/microL.
The Loss of Tafazzin Transacetylase Activity Is Sufficient to Drive Testicular Infertility.
J Dev Biol
November 2024
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Barth syndrome (BTHS) is a rare, infantile-onset, X-linked mitochondriopathy exhibiting a variable presentation of failure to thrive, growth insufficiency, skeletal myopathy, neutropenia, and heart anomalies due to mitochondrial dysfunction secondary to inherited TAFAZZIN transacetylase mutations. Although not reported in BTHS patients, male infertility is observed in several () mouse alleles and in a mutant. Herein, we examined the male infertility phenotype in a BTHS-patient-derived point-mutant knockin mouse () allele that expresses a mutant protein lacking transacetylase activity.
View Article and Find Full Text PDFFlavopiridol restores granulopoiesis in experimental models of severe congenital neutropenia.
Mol Ther
November 2024
Department of Oncology, Hematology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, 72076 Tuebingen, Germany; Gene and RNA Therapy Center (GRTC), Tuebingen University, 72076 Tuebingen, Germany. Electronic address:
Severe congenital neutropenia (CN) patients require life-long treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), but some show no response. We sought to establish a therapy for CN that targets signaling pathways causing maturation arrest of granulocytic progenitors. We developed an isogenic induced pluripotent stem cell (iPSC) in vitro model of CN associated with ELANE mutations (ELANE-CN) and performed an in silico drug repurposing analysis of the transcriptomics of iPSC-generated hematopoietic stem and progenitor cells.
View Article and Find Full Text PDFWe have identified a new inherited bone marrow (BM) failure syndrome with severe congenital neutropenia (CN) caused by autosomal recessive mutations in the coatomer protein complex I (COPI) subunit zeta 1 (COPZ1) gene. A stop-codon COPZ1 mutation and a missense mutation were found in three patients from two unrelated families. While two affected siblings with a stop-codon COPZ1 mutation suffered from congenital neutropenia (CN) that involves other hematological lineages, and non-hematological tissues, the patient with a missense COPZ1 mutation had isolated neutropenia.
View Article and Find Full Text PDFConstitutional Mosaic Pericentromeric Trisomy 8 in a Female Patient With Aplastic Anemia.
Am J Med Genet A
December 2024
Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Aplastic anemia, characterized by pancytopenia and hypoplastic bone marrow, is associated with various acquired cytogenetic abnormalities, including trisomy 8, in 4%-15% of patients. Constitutional mosaic trisomy 8 notably increases the risks for cytopenia and myeloid malignancies. Duplications near chromosome 8 centromere are associated with developmental delays, autism, and trisomy 8p11.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!