STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation
Open accessAbstract
STAT3 has been described as an essential component of G-CSF-driven cell proliferation and granulopoiesis. This notion was tested by conditional gene ablation in transgenic mice. Contrary to expectation, granulocytes developed from STAT3 null bone marrow progenitors, and STAT3 null neutrophils displayed mature effector functions. Rather than a deficit in granulopoiesis, mice lacking STAT3 in their hematopoietic progenitors developed neutrophilia, and bone marrow cells were hyperresponsive to G-CSF stimulation. These studies provide direct evidence for STAT3-independent granulopoiesis and suggest that STAT3 directs a negative feedback loop necessary for controlling neutrophil numbers, possibly through induced expression of the signaling inhibitor, SOCS3.
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Hematopoietic progenitor-specific STAT3 knockout leaves basal hematopoiesis unaltered but impairs stem cell regeneration after 5-FU.
“Unaltered basal hematopoiesis; impaired stem cell regeneration after 5-FU”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Lee et al., 2002
The Introduction describes STAT3 deletion in hematopoietic progenitors, and the granulopoiesis results report similar total white-cell counts and numbers of general precursors in controls and knockout mice. But basal hematopoiesis was not wholly unaltered: the mutants had increased neutrophils. The paper describes treating mice with 5-fluorouracil, but the located passage does not report impaired stem-cell regeneration afterward (page unavailable in our copy). (LLM, conf=0.85)
Experimental — accuracy not yet measuredModestly increased numbers of peripheral blood mononuclear cells with myeloid markers were seen in TTI-101-treated animals, which phenocopied mice with myeloid-lineage-specific deletion of STAT3.
“In addition, modestly increased numbers of peripheral blood mononuclear cells with myeloid markers were seen in treated animals, which phenocopied mice with myeloid-lineage–specific deletion of STAT3 (Lee et al., 2002).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Lee et al., 2002
In “Granulopoiesis in the Absence of STAT3” (page unavailable), Lee et al. report an increased percentage of peripheral-blood neutrophils in STAT3-deficient mice, supporting the claimed resemblance in myeloid-cell phenotype. However, they studied Mx-Cre-mediated STAT3 deletion in hematopoietic progenitors, not myeloid-lineage-specific deletion, and did not report increased numbers of peripheral blood mononuclear cells bearing myeloid markers. The treated animals’ result belongs to the citing study, not Lee et al. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSTAT3 is not required for basal granulopoiesis.
“STAT3 was found not to be required for basal granulopoiesis”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Lee et al., 2002
Exposure of mice to TTI-101 has modest and expected effects on T cell subsets and myeloid cells.
“Exposure of mice to TTI-101 has modest and expected effects on T cell subsets and myeloid cells.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Lee et al., 2002
The Granulopoiesis in the Absence of STAT3 section (Table 1; page unavailable) reports neutrophil and lymphocyte counts after induced STAT3 deletion in mice, not after TTI-101 exposure. Searches for TTI-101 and T-cell subsets found no passage addressing the claimed treatment effects. (LLM, conf=0.77)
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References 45 · Cited by 242
Research works printed but not linked: 2
- Liu, F., Wu, H.Y., Wesselschmidt, R., Kornaga, T., and Link, D.C. Takeda, K., Noguchi, K., Shi, W., Tanaka, T., Matsumoto, M., Yoshi- (1996). Impaired production and increased apoptosis of neutrophils da, N., Kishimoto, T., and Akira, S. (1997). Targeted disruption of in granulocyte colony-stimulating factor receptor-deficient mice. Im- the mouse Stat3 gene leads to early embryonic lethality. Proc. Natl. munity 5, 491-501. Acad. Sci. USA 94, 3801-3804.
- Raz, R., Lee, C.K., Cannizzaro, L.A., d'Eustachio, P., and Levy, D.E. (1999). Essential role of STAT3 for embryonic stem cell pluripotency. Proc. Natl. Acad. Sci. USA 96, 2846-2851.
- Authors
- Lee, C.-K., Raz, R., Gimeno, R., Gertner, R., Wistinghausen, B., Takeshita, K., DePinho, R. A., & Levy, D. E.
- Affiliations
- NYU Langone Health (US)
- Harvard University (US)
- Corresponding author
- Levy, David E.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2002-07
- Volume
- 17
- Issue
- 1
- Pages
- 63-72
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2004527202
- Cited by
- 242
- References
- 45
- Citations by year
- 2025: 5 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 9 · 2020: 4 · 2019: 10 · 2018: 3 · 2017: 6 · 2016: 12 · 2015: 6 · 2014: 9 · 2013: 12 · 2012: 10
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- STAT3, granulopoiesis, granulocyte colony-stimulating factor, granulocytic differentiation, neutrophilia, bone marrow progenitor cells, negative feedback loop, SOCS3, conditional gene deletion, hematopoiesis
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Cell Differentiation, Cell Division, Cells, Cultured, DNA-Binding Proteins, Granulocytes, Hematopoiesis, Hematopoietic Stem Cells, Mice, Transgenic, Neutrophils, Repressor Proteins, Transcription Factors, Protein Biosynthesis, Signal Transduction, Trans-Activators, Granulocyte Colony-Stimulating Factor, Mice, Knockout, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice
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