Cited by 115Blood disorders and treatmentsImmunodeficiency and Autoimmune DisordersNeutropenia and Cancer Infections

Mouse models of neutropenia reveal progenitor-stage-specific defects

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Muench, David E., Olsson, Andre, Ferchen, Kyle, Pham, Giang, Serafin, Rachel A., Chutipongtanate, Somchai, Dwivedi, Pankaj, Song, Baobao +14 more·2020·Nature

Abstract

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes 1, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.

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  • The coupling of genetic discoveries with single-cell genomic tools greatly increases potential to further refine understanding of hematopoiesis, as has been done in recent studies of congenital neutropenia.

    “The coupling of these genetic discoveries with the single-cell genomic tools we have discussed in this review greatly increases our potential to further refine our understanding of hematopoiesis, as has been done elegantly in recent studies of congenital neutropenia (Muench et al., 2020).”

    From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Muench et al., 2020

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  1. [2]Gilbert SF Developmental Biology, 6th edition. (Sinauer Associates, 2000).

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Authors
Muench, D. E., Olsson, A., Ferchen, K., Pham, G., Serafin, R. A., Chutipongtanate, S., Dwivedi, P., Song, B., Hay, S., Chetal, K., Trump-Durbin, L. R., Mookerjee-Basu, J., Zhang, K., Yu, J. C., Lutzko, C., Myers, K. C., Nazor, K. L., Greis, K. D., Kappes, D. J., Way, S. S., Salomonis, N., & Grimes, H. L.
Affiliations
  • Cincinnati Children's Hospital Medical Center (US)
  • Mahidol University (TH)
  • University of Cincinnati (US)
  • University of California San Diego (US)
  • BioLegend (United States) (US)
  • Fox Chase Cancer Center (US)
Corresponding author
  • Salomonis, Nathan
  • Grimes, H. Leighton
Venue
Nature
Published
2020-04-22
Volume
582
Issue
7810
Pages
109-114
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W3018353191
Cited by
115
References
35
Citations by year
2026: 11 · 2025: 17 · 2024: 12 · 2023: 17 · 2022: 20 · 2021: 29 · 2020: 8
FWCI
10.83
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (DK78392, AR‐47363)
  • National Heart, Lung, and Blood Institute (R01HL122661)
  • National Cancer Institute (T32CA117846)
  • National Institute of Allergy and Infectious Diseases (DP1AI131080)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK090971, P30DK078392)
  • National Institute of Environmental Health Sciences (T32ES007250)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR047363)
  • National Center for Research Resources (S10RR027015)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Health Sciences › Medicine › Oncology › Neutropenia and Cancer Infections
Keywords
severe congenital neutropenia, GFI1, mouse model, granulopoiesis, genetic rescue
MeSH terms
Animals, Candida albicans, Disease Models, Animal, DNA-Binding Proteins, Female, Humans, Immunity, Innate, Male, Mice, Transgenic, Mutation, Neutropenia, Neutrophils, Transcription Factors, Cell Lineage, Granulocyte Precursor Cells, Mice

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