Abstract
Little is known about carcinogenesis following low-dose-rate (LDR) irradiation. Cancer is originated from cancer stem cell with self-renewal and multipontency. We tried to elucidate at which cell differentiation stage cells were transformed into leukemic stem cells (LSCs) by LDR irradiation. Three groups of C3H/He mice were irradiated with 8, 4 and 3 Gy at dose rates of 20 mGy/day, 400 mGy/day and 1.0 Gy/min, respectively. Radiation-induced and spontaneous leukemias were compared regarding chromosome aberration detected by array CGH analysis, CD-antigen expression profiles by FACS and identification of LSC by transplantation. Array CGH showed that approximately 50% of leukemias in all groups commonly had 30Mb hemizygous deletion nearby centromere of chromosome 7. In contrast, hemizygous deletion of PU.1, a leukemia-related gene, on chromosome 2 was found in a dose-rate-dependent manner in 6% of spontaneous leukemias in non-irradiated mice, and 30%, 56%, and 90% of leukemias from mice irradiated respectively at 20 mGy/day, 400 mGy/day and 1.0 Gy/min. The leukemias with hemizygous PU.1 deletion (PU.1del-leukemias) frequently had mutation on the remaining allele of PU.1. PU.1del-leukemias showed an increase in common myeloid progenitors (CMPs), while leukemias without PU.1 mutation (PU.1wt-leukemias) showed an increase in common lymphoid progenitors (CLPs). Furthermore, transplantation assay by injection of each cell populations showed that LSCs were present in subpopulations of hematopoietic stem cells (HSCs) and CMPs in PU.1del leukemias, while LSCs were in subpopulations of CLPs and granulocytes in PU.1wt-leukemias. Our results indicate differences in the origins of LSCs and gene mutations responsible for radiation leukemogenesis with different dose-rates. This study was performed under contract with the Aomori Prefectural Government, Japan.
