Subversion of T lineage commitment by PU.1 in a clonal cell line system
Open accessAbstract
Specification of mammalian T lymphocytes involves prolonged developmental plasticity even after lineage-specific gene expression begins. Expression of transcription factor PU.1 may maintain some myeloid-like developmental alternatives until commitment. Commitment could reflect PU.1 shutoff, resistance to PU.1 effects, and/or imposition of a suicide penalty for diversion. Here, we describe subclones from the SCID.adh murine thymic lymphoma, adh.2C2 and adh.6D4, that represent a new tool for probing these mechanisms. PU.1 can induce many adh.2C2 cells to undergo diversion to a myeloid-like phenotype, in an all-or-none fashion with multiple, coordinate gene expression changes; adh.6D4 cells resist diversion, and most die. Diversion depends on the PU.1 Ets domain but not on known interactions in the PEST or Q-rich domains, although the Q-rich domain enhances diversion frequency. Protein kinase C/MAP kinase stimulation can make adh.6D4 cells permissive for diversion without protecting from suicide. These results show distinct roles for regulated cell death and another stimulation-sensitive function that establishes a threshold for diversion competence. PU.1 also diverts normal T-cell precursors from wild type or Bcl2-transgenic mice to a myeloid-like phenotype, upon transduction in short-term culture. The adh.2C2 and adh.6D4 clones thus provide an accessible system for defining mechanisms controlling developmental plasticity in early T-cell development.
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Re-expression of PU.1 after T-cell commitment turns on myeloid genes and can transform later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells.
“re-expression of PU.1 after T-cell commitment turns on myeloid genes and readily transforms later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells (46–50).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [47]
The Results report that PU.1 induced myeloid-associated genes in a pro-T cell line, and the section on diverted gene expression reports that committed DN3 thymocytes acquired Mac1 expression and non-lymphoid morphology after PU.1 was restored. The paper describes this as diversion to a myeloid-like phenotype, not demonstrated transformation of later pro-T cells into dendritic cells, macrophages, or promyelocytic-like cells. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredScid.adh.2C2 cells are similar to developmentally arrested committed DN3 pro-T cells and lack endogenous PU.1.
“These cells were a subclone derived from the Scid.adh cell line (87) and are similar to developmentally arrested versions of committed DN3 pro-T cells, lacking any expression of endogenous PU.1 (47).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [47]
The Introduction identifies adh.2C2 as a SCID.adh subclone with a DN3-like phenotype, and the Results describe the SCID.adh cells as arrested at a developmental stage. The Introduction says the subclone has ‘little if any’ endogenous PU.1 expression; the DN3-comparison section says it does not express PU.1 significantly. Those passages support very low expression, but not the categorical claim that it lacks any expression. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe gene network switch underlies stochastic, switch-like behavior of individual pro-T or Scid.adh.2C2 cells when forced to express high-level PU.1.
“this gene network switch underlies the stochastic, switch-like behavior of individual pro-T or Scid.adh.2C2 cells when forced to express high-level PU.1 (47, 58).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [47]
The Results and Discussion (page unavailable) describe a discontinuous, all-or-none response to forced PU.1 expression in individual SCID.adh cells, including the adh.2C2 clone. The section “Diversion: a discrete state of a bistable network” interprets this as a shift in gene-regulatory-network state, but the paper says the network controlling that choice remains to be elucidated; it does not establish that switch as the mechanism underlying the behavior in primary pro-T cells. (LLM, conf=0.84)
Experimental — accuracy not yet measuredScid.adh.2C2 cells respond in an all-or-none way to forced PU.1, coordinately upregulating myeloid/dendritic genes and downregulating T-cell genes in a discrete fraction increasing with PU.1 levels.
“They respond in an all-or-none way to forced expression of PU.1, coordinately upregulating myeloid- or dendritic-cell associated genes and downregulating T-cell genes in a discrete fraction of the cells that increases with increasing levels of PU.1 (47, 58)”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [47]
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References 61 · Cited by 54
Research works printed but not linked: 4
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- Authors
- Dionne, C. J., Tse, K. Y., Weiss, A. H., Franco, C. B., Wiest, D. L., Anderson, M. K., & Rothenberg, E. V.
- Affiliations
- California Institute of Technology (US)
- Fox Chase Cancer Center (US)
- Corresponding author
- Rothenberg, Ellen V.
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2005-04
- Volume
- 280
- Issue
- 2
- Pages
- 448-466
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W2046423539
- Cited by
- 54
- References
- 61
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 2 · 2019: 5 · 2018: 4 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 5
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- California Institute of Technology
- National Institutes of Health
- National Cancer Institute (R01CA090233, CA90233)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- PU.1, developmental plasticity, regulated cell death, ETS domain, protein kinase C, mitogen-activated protein kinase, Bcl-2, T cell precursors, clonal cell lines, transcription factor function
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Cell Line, Cloning, Molecular, Flow Cytometry, Hematopoietic Stem Cells, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Fluorescence, Models, Biological, Phenotype, Protein Kinase C, Proto-Oncogene Proteins, Retroviridae, T-Lymphocytes, Thymus Gland, Time Factors, Receptors, Interleukin-2, Trans-Activators, Mice, SCID, Protein Structure, Tertiary, Gene Expression Regulation, Developmental, Cell Lineage, Transgenes, Reverse Transcriptase Polymerase Chain Reaction, MAP Kinase Signaling System, Myeloid Cells, Cell Line, Tumor, Cell Proliferation, Mice
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