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Updated: Jan 2, 2026
Characterization of Thymic Settling Progenitors in the Mouse Embryo Using In Vivo and In Vitro Assays
Published on: June 9, 2015
Loss of Setd4 delays radiation-induced thymic lymphoma in mice
Xing Feng1, Huimei Lu1, Jingyin Yue1
1Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
Abstract:
Radiation-induced lymphomagenesis results from a clonogenic lymphoid cell proliferation due to genetic alterations and immunological dysregulation. Mouse models had been successfully used to identify risk and protective factors for radiation-induced DNA damage and carcinogenesis. The mammalian SETD4 is a poorly understood putative methyl-transferase. Here, we report that conditional Setd4 deletion in adult mice significantly extended the survival of radiation-induced T-lymphoma. However, in Tp53 deficient mice, Setd4 deletion did not delay the radiation-induced lymphomagenesis although it accelerated the spontaneous T-lymphomagenesis in non-irradiated mice. The T-lymphomas were largely clonogenic in both Setd4flox/flox and Setd4Δ/Δ mice based on sequencing analysis of the T-cell antigen β receptors. However, the Setd4Δ/Δ T-lymphomas were CD4+/CD8+ double positive, while the littermate Setd4flox/floxtumor were largely CD8+ single positive. A genomic sequencing analysis on chromosome deletion, inversion, duplication, and translocation, revealed a larger contribution of inversion but a less contribution of deletion to the overall chromosome rearrangements in the in Setd4Δ/Δ tumors than the Setd4flox/flox tumors. In addition, the Setd4flox/flox mice died more often from the large sizes of primary thymus lymphoma at earlier time, but there was a slight increase of lymphoma dissemination among peripheral organs in Setd4Δ/Δ at later times. These results suggest that Setd4 has a critical role in modulating lymphomagenesis and may be targeted to suppress radiation-induced carcinogenesis.
Insights
Deleting the SetD4 gene in mice extended survival from radiation-induced T-cell lymphoma. SetD4 influences lymphoma development and chromosome alterations, suggesting it as a target for cancer prevention.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Radiation exposure can cause T-cell lymphoma through genetic changes and immune system disruption.
- Mouse models are crucial for understanding radiation-induced DNA damage and cancer development.
- The mammalian SETD4 gene's function in methyl-transferase activity is largely unknown.
Purpose of the Study:
- To investigate the role of SETD4 in radiation-induced lymphomagenesis.
- To determine if SETD4 deletion affects T-lymphoma development and progression in mice.
- To explore SETD4's impact on genetic alterations during lymphomagenesis.
Main Methods:
- Conditional deletion of the Setd4 gene in adult mice.
- Irradiation of mice to induce T-lymphoma.
- Sequencing of T-cell receptor beta genes to assess clonality.
- Genomic sequencing to analyze chromosomal rearrangements (deletion, inversion, duplication, translocation).
- Comparison of tumor characteristics (cell surface markers, dissemination) between Setd4-deleted and control mice.
Main Results:
- Conditional Setd4 deletion significantly extended survival in radiation-induced T-lymphoma models.
- In Tp53-deficient mice, Setd4 deletion did not delay radiation-induced lymphomagenesis but accelerated spontaneous T-lymphomagenesis.
- Setd4-deleted T-lymphomas exhibited a CD4+/CD8+ double-positive phenotype, unlike CD8+ single-positive Setd4-wildtype tumors.
- Setd4 deletion led to increased chromosomal inversions and decreased deletions in tumors.
- Setd4-deleted tumors showed delayed primary tumor growth but increased dissemination to peripheral organs.
Conclusions:
- SetD4 plays a critical role in modulating lymphomagenesis, particularly in response to radiation.
- Targeting SETD4 may offer a strategy for suppressing radiation-induced carcinogenesis.
- The findings highlight SETD4's complex involvement in both spontaneous and radiation-induced T-cell lymphoma development.
