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DNA Repair (Amst). 2020 Feb;86:102754. doi: 10.1016/j.dnarep.2019.102754. Epub 2019 Nov 25.

Loss of Setd4 delays radiation-induced thymic lymphoma in mice.

Author information

1
Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
2
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
3
Center for Systems and Computational Biology, Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ 08901, USA.
4
Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, 195 Little Albany Street, New Brunswick, NJ 08903, USA. Electronic address: shenzh@cinj.rutgers.edu.

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.

KEYWORDS:

Chromosome rearrangement; Genomic instability; Radiation carcinogenesis; Setd4; T-cell lymphoma

PMID:
31794893
PMCID:
PMC6960333
[Available on 2021-02-01]
DOI:
10.1016/j.dnarep.2019.102754
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