Trial reportThe Journal of clinical investigation2015
Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells.
Trial report in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
46 citing papers in PubMed, 81 citations in OpenAlex.
- Neutrophil extracellular traps formation driven by novel ELANE mutations in cyclic neutropenia patients.Genes and immunity · 2026Article
- Germ line LCP1 mutations cause immunodeficiency with neutropenia, monocytopenia, lymphopenia, and defective cytokinesis.Blood advances · 2026Article
- CRISPR-based therapeutic genome editing for inherited blood disorders.Nature reviews. Drug discovery · 2025Review
- ModelingJournal of cellular immunology · 2025Article
- G-CSF resistance of ELANE-mutant neutropenia depends on SERF1-containing truncated-neutrophil elastase aggregates.The Journal of clinical investigation · 2024Article
- Inducible pluripotent stem cells to study human mast cell trajectories.Mucosal immunology · 2024Article
- De Novo Deep Intron ELANE Mutation Resulting in Severe Congenital Neutropenia.Journal of clinical immunology · 2024Article
- Differential transcriptional control of hematopoiesis in congenital and cyclic neutropenia patients harboringHaematologica · 2024Article
- The metabolic basis of inherited neutropenias.British journal of haematology · 2024Review
- 'Off the shelf' immunotherapies: Generation and application of pluripotent stem cell-derived immune cells.Cell proliferation · 2023Review
- Mutant allele knockout with novel CRISPR nuclease promotes myelopoiesis in ELANE neutropenia.Molecular therapy. Methods & clinical development · 2022Article
- Review
- Dissecting ELANE neutropenia pathogenicity by human HSC gene editing.Cell stem cell · 2021Article
- PML-controlled responses in severe congenital neutropenia with ELANE-misfolding mutations.Blood advances · 2021Article
- G-CSF shifts erythropoiesis from bone marrow into spleen in the setting of systemic inflammation.Life science alliance · 2021Article
- The Use of Induced Pluripotent Stem Cells to Study the Effects of Adenosine Deaminase Deficiency on Human Neutrophil Development.Frontiers in immunology · 2021Article
- CRISPR-Cas9-Mediated ELANE Mutation Correction in Hematopoietic Stem and Progenitor Cells to Treat Severe Congenital Neutropenia.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- Article
- Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.The Journal of allergy and clinical immunology · 2020Article
- NovelJournal of pediatric genetics · 2020Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Severe congenital neutropenia (SCN) is often associated with inherited heterozygous point mutations in ELANE, which encodes neutrophil elastase (NE). However, a lack of appropriate models to recapitulate SCN has substantially hampered the understanding of the genetic etiology and pathobiology of this disease. To this end, we generated both normal and SCN patient-derived induced pluripotent stem cells (iPSCs), and performed genome editing and differentiation protocols that recapitulate the major features of granulopoiesis. Pathogenesis of ELANE point mutations was the result of promyelocyte death and differentiation arrest, and was associated with NE mislocalization and activation of the unfolded protein response/ER stress (UPR/ER stress). Similarly, high-dose G-CSF (or downstream signaling through AKT/BCL2) rescues the dysgranulopoietic defect in SCN patient-derived iPSCs through C/EBPβ-dependent emergency granulopoiesis. In contrast, sivelestat, an NE-specific small-molecule inhibitor, corrected dysgranulopoiesis by restoring normal intracellular NE localization in primary granules; ameliorating UPR/ER stress; increasing expression of CEBPA, but not CEBPB; and promoting promyelocyte survival and differentiation. Together, these data suggest that SCN disease pathogenesis includes NE mislocalization, which in turn triggers dysfunctional survival signaling and UPR/ER stress. This paradigm has the potential to be clinically exploited to achieve therapeutic responses using lower doses of G-CSF combined with targeting to correct NE mislocalization.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.