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Updated: May 29, 2026
Retroviral Transduction of T-cell Receptors in Mouse T-cells
Published on: October 22, 2010
TCR-dependent transformation of mature memory phenotype T cells in mice
Xi Wang1, Miriam B F Werneck, Boris G Wilson
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Abstract:
A fundamental goal in cancer research is the identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth, as this has the potential to reveal therapeutic targets. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies. However, the identity of the cells in which mature lymphoid neoplasms are initiated remains unclear. Here, we investigate the origin of peripheral T cell lymphomas using mice in which Snf5, a chromatin remodelling-complex subunit with tumor suppressor activity, could be conditionally inactivated in developing T cells. In this model of mature peripheral T cell lymphomas, the cell of origin was a mature CD44hiCD122loCD8⁺ T cell that resembled a subset of memory cells that has capacity for self-renewal and robust expansion, features shared with stem cells. Further analysis showed that Snf5 loss led to activation of a Myc-driven signaling network and stem cell transcriptional program. Finally, lymphomagenesis and lymphoma proliferation depended upon TCR signaling, establishing what we believe to be a new paradigm for lymphoid malignancy growth. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells are associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers.
Insights
Researchers identified mature T cells, resembling memory cells, as the origin of peripheral T cell lymphomas. Snf5 (Swi/Snf related, Matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2) loss activated stem cell programs, and T cell receptor (TCR) signaling was crucial for lymphoma growth.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Identifying cancer-initiating cells and pathways is crucial for developing targeted therapies.
- While stem cells are implicated in some lymphoid malignancies, the origin of mature lymphoid neoplasms remains unclear.
- Peripheral T cell lymphomas are aggressive cancers with poorly understood origins.
Purpose of the Study:
- To investigate the cell of origin for mature peripheral T cell lymphomas.
- To elucidate the molecular mechanisms driving lymphomagenesis in this model.
- To explore potential therapeutic strategies targeting lymphoma growth.
Main Methods:
- Conditional inactivation of the Snf5 gene in developing T cells of mice.
- Characterization of lymphoma-initiating cells using cell surface markers (CD44, CD122, CD8).
- Analysis of gene expression, including Myc signaling and stem cell transcriptional programs.
- Assessment of the role of T cell receptor (TCR) signaling in lymphomagenesis.
Main Results:
- Mature CD44hiCD122loCD8+ T cells, resembling memory cells with stem-like properties, were identified as the cell of origin.
- Snf5 loss activated a Myc-driven signaling network and a stem cell transcriptional program.
- Lymphomagenesis and proliferation were dependent on TCR signaling, establishing a new paradigm for lymphoid malignancy growth.
Conclusions:
- Memory T cells with self-renewal and expansion capacities are vulnerable to oncogenic transformation.
- TCR signaling is a critical pathway for the growth of these peripheral T cell lymphomas.
- Targeting TCR signaling may offer a novel therapeutic approach for these lethal cancers.
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