Abstract
High dose radiation significantly induces acute myeloid leukemia (AML) in C3H/He Nrs mice. The AML cells had the hemizygous deletion of chromosome 2. To detect the mutations of oncogenes related to radiation-induced AML, we analyzed the changes of whole-genomic DNA copy-numbers using array CGH, and the RNA expressions by RT-PCR and real-time PCR. The partial gain of chromosome 6 in 35 AMLs with the deletion of chromosome 2 (del(2)+ AML) and that of chromosome 15 in 4 AMLs without deletion of chromosome 2 (del(2)- AML) were observed, respectively. The point mutations in the remaining PU.1 allele were observed in 83% of del(2)+ AMLs, but not in del(2)- AMLs. AMLs induced in syngeneic C3H mice after transplantation of the primary AMLs, showed the similar chromosomal aberrations as well as the gain of chromosome X.
Analyses for the RNA expressions of 24 genes, including PU.1, AML1 and others within the altered chromosomal regions indicated that expressions of GATA1, M-CSFR and Wnt5b were lower in both del(2)+ AMLs and del(2)- AMLs than those in normal spleen cells. In contrast, expressions of PU.1 and C-myc were up-regulated more highly in del(2)+ AMLs than del(2)- AMLs. These results suggest a kind of regulation mechanism in which the expression of PU.1 on the deleted hemizygous allele can be complemented by up-regulation of the remaining allele. This work was supported by a grant from Aomori prefecture, Japan.
