Influence of low-dose radiation on leukemia development in genetic predisposition in a mouse model

Ionizing radiation is an accepted risk factor for childhood leukemia development. However, the significance of weak ionizing radiation in the low dose range is still unclear. The aim of this research project was to experimentally test whether exposure to low-dose radiation can cause oncogenic mutations (as a so-called second "hit") in the Sca1-ETV6-RUNX1 mouse model, which carries the most common preleukemic translocation t(12;21) coding for the chimeric transcription factor ETV6-RUNX1 found in children. Precursor B-cell acute lymphoblastic leukemia (pB-ALL) developed in Sca1-ETV6-RUNX1 mice irradiated once at four weeks of age with an exact dose of at least 0.5 Gy from a gamma radiation source (Cs-137) (0.5 Gy, n=3/30; 2 Gy, n=4/30). Exposure-related somatic mutations in these pB-ALL involved (1) hot-spot regions in known cancer genes (Jak1, Jak3, Ptpn11, Kras), (2) genes that were also mutated in human ETV6-RUNX1-positive pB-ALL (Atm, Sh2b3, Ptpn11, Kras), (3) pB-ALL predisposition genes (Sh2B3, Ptpn11), and (4) other known cancer genes. Due to the small number of tumors and somatic SNV, no specific radiation-induced mutation signature could be identified. Larger cohorts or mouse models with higher tumorigenicity, together with whole-genome sequencing and complementary omics analyses, could generate larger data sets in the future and provide a comprehensive picture of specific t(12;21)-associated secondary genomic alterations resulting from radiation.