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Subversion of T lineage commitment by PU.1 in a clonal cell line system
Christopher J Dionne1, Kevin Y Tse, Angela H Weiss
1Division of Biology 156-29, California Institute of Technology, Pasadena, 91125 USA.
Developmental Biology
|May 11, 2005
Summary
Transcription factor PU.1 drives T-cell plasticity, diverting precursors to myeloid fates. New lymphoma clones reveal distinct roles for cell death and signaling in controlling this developmental switch.
Area of Science:
- Immunology
- Developmental Biology
- Cell Biology
Background:
- Mammalian T lymphocyte development exhibits plasticity, allowing alternative cell fates even after lineage commitment begins.
- Transcription factor PU.1 may maintain myeloid-like developmental options in T-cell precursors before they commit to the T-cell lineage.
- Commitment to the T-cell lineage might involve shutting off PU.1, developing resistance to its effects, or undergoing programmed cell death upon diversion.
Purpose of the Study:
- To investigate the mechanisms controlling developmental plasticity in early T-cell development.
- To utilize novel murine thymic lymphoma subclones (adh.2C2 and adh.6D4) as tools to probe PU.1-mediated developmental diversion.
- To define the roles of regulated cell death and signaling pathways in T-cell precursor commitment.
Main Methods:
- Generation and characterization of SCID.adh murine thymic lymphoma subclones adh.2C2 and adh.6D4.
- Induction of myeloid-like diversion in T-cell precursors using PU.1 expression.
- Analysis of PU.1 domain requirements (Ets, PEST, Q-rich) for diversion.
- Stimulation of Protein Kinase C/MAP kinase pathways to assess effects on diversion and cell death.
- Transduction of normal T-cell precursors (wild type and Bcl2-transgenic) with PU.1.
Main Results:
- PU.1 successfully induced myeloid-like diversion in adh.2C2 cells, characterized by coordinate gene expression changes.
- PU.1 induced cell death in adh.6D4 cells, which resisted diversion, highlighting distinct cellular responses.
- Diversion capability was dependent on the PU.1 Ets domain, enhanced by the Q-rich domain, and modulated by Protein Kinase C/MAP kinase signaling.
- PU.1 also diverted normal T-cell precursors to a myeloid-like phenotype in short-term culture.
Conclusions:
- The adh.2C2 and adh.6D4 clones serve as valuable models for studying developmental plasticity in T-cell precursors.
- Distinct cellular mechanisms, including regulated cell death and signaling-dependent thresholds, govern T-cell lineage commitment.
- PU.1 plays a critical role in T-cell developmental plasticity, capable of diverting precursors towards a myeloid fate.