Reduction in PU.1 activity results in a block to B-cell development, abnormal myeloid proliferation, and neonatal lethality
Open accessAbstract
Objective It has been demonstrated that high concentration of the transcription factor PU.1 (encoded by Sfpi1) promotes macrophage development, whereas low concentration induces B-cell development in vitro. This has led to the hypothesis that lower levels of PU.1 activity are required for B cell than for macrophage development in vivo. We utilized an allele of Sfpi1 (termed BN) with a mutation in the first coding exon, which resulted in a reduction of PU.1 expression in order to test this hypothesis. Materials and methods Using gene targeting in embryonic stem cells, two ATG-start site codons of PU.1 were mutated, resulting in reduced PU.1 expression originating from a third start codon. Mice were assayed for phenotypic abnormalities using fluorescence-activated cell sorting, microscopy, and colony-forming ability. In addition, isolated cells were tested for their differentiation potential in vitro and in vivo. Results Lymphoid and myeloid cells derived from cultured Sfpi1(BN/BN) fetal liver cells had reduced levels of PU.1 expression and activity. B-cell development was intrinsically blocked in cells isolated from Sfpi1(BN/BN) mice. In addition, myeloid development was impaired in Sfpi1(BN/BN) fetal liver. However, neonatal Sfpi1(BN/BN) mice had a dramatic expansion and infiltration of immature myeloid cells. Conclusion Contrary to our original hypothesis, high levels of PU.1 activity are required to induce both myeloid and B-cell development. In addition, neonatal mice homozygous for the hypomorphic allele acquire a myeloproliferative disorder and die within 1 month of age.
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PU.1 action is important or indispensable for sustained generation of all known hematopoietic precursors with lymphoid developmental potentials.
“its action is also important or indispensable for sustained generation of all known hematopoietic precursors that have lymphoid developmental potentials (1–9).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [5]
The Abstract says PU.1 is required for lymphoid-lineage development, and the Discussion says high PU.1 activity is essential at the earliest stages of B-cell specification. The paper does not establish that PU.1 is important or indispensable for sustained generation of all known hematopoietic precursors with lymphoid developmental potential; its stated conclusion is narrower. (LLM, conf=0.85)
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References 29 · Cited by 49
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- Authors
- Houston, I. B., Kamath, M. B., Schweitzer, B. L., Chlon, T. M., & DeKoter, R. P.
- Affiliations
- University of Cincinnati (US)
- Corresponding author
- DeKoter, Rodney P.
- Venue
- Experimental Hematology
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 35
- Issue
- 7
- Pages
- 1056-1068
- ISSN
- 0301-472X (ISSN-L)
- PMC
- PMC1975786
- OpenAlex
- W1999732051
- Cited by
- 49
- References
- 29
- Citations by year
- 2025: 2 · 2022: 1 · 2021: 6 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 7 · 2012: 3
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Experimental Hematology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Miami
- University of Cincinnati
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI052175, AI052175)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- PU.1, B cell development, myeloid development, myeloproliferative neoplasms, neonatal lethality, hypomorphic allele, transcription factor dosage, macrophage development, fetal liver, hematopoiesis
- MeSH terms
- Proto-Oncogene Protein Spi-1, Alleles, Animals, Animals, Newborn, B-Lymphocytes, Cells, Cultured, Humans, Mice, Inbred C57BL, Myeloproliferative Disorders, Proto-Oncogene Proteins, Trans-Activators, Myelopoiesis, Cell Proliferation, Mice
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