Characterizing the role of Phlda3 in the development of acute toxicity and malignant transformation of hematopoietic cells induced by total-body irradiation in mice.

The tumor suppressor p53 is a transcriptional factor that plays a crucial role in controlling acute toxicity and long-term malignant transformation of hematopoietic cells induced by genotoxic stress such as ionizing radiation. Among all transcriptional targets of p53, one gene that is robustly induced by radiation is the pleckstrin homology domain-only protein Phlda3. However, the role that Phlda3 plays in regulating the response of hematopoietic cells to radiation is unknown.

Whole-Exome Sequencing of Radiation-Induced Thymic Lymphoma in Mouse Models Identifies Notch1 Activation as a Driver of p53 Wild-Type Lymphoma.

Mouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-cell lymphoblastic leukemia/lymphoma. Here we aimed to identify key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53, and Kras mice were not observed to harbor significantly higher numbers of nonsynonymous somatic mutations compared with thymic lymphomas from unirradiated p53 mice.

Transplantation of Unirradiated Bone Marrow Cells after Total-Body Irradiation Prevents the Development of Thymic Lymphoma in Mice through Niche Competition.

Mouse models of radiation-induced thymic lymphoma are commonly used to study the biological effects of total-body irradiation (TBI) on the formation of hematologic malignancies. It is well documented that radiation-induced thymic lymphoma can be inhibited by protecting the bone marrow (BM) from irradiation; however, the mechanisms underlying this phenomenon are poorly understood. Here, we aimed to address this question by performing transplantation of BM cells from genetically engineered mice that have defects in tumor immunosurveillance or occupying different thymic niches.

Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma.

Cancer development is influenced by hereditary mutations, somatic mutations due to random errors in DNA replication, or external factors. It remains unclear how distinct cell-intrinsic and -extrinsic factors impact oncogenesis within the same tissue type. We investigated murine soft tissue sarcomas generated by oncogenic alterations (KrasG12D activation and p53 deletion), carcinogens (3-methylcholanthrene [MCA] or ionizing radiation), and in a novel model combining both factors (MCA plus p53 deletion).