Figure 3.

DNA replication during S-phase - therapeutic target and source of mutation. Highest accuracy during DNA replication is essential to guarantee genomic integrity. In case of perturbations during the replication process or in case of DNA double-strand breakage, an ATM-driven DNA damage response (originating from DNA lesions which are shown at the top) leads to inihibiton of Cdk2 (shown in the lower part) via Cdc25 to block cell cycle progression. Interference with DNA replication by cytarabine or induction of DNA double-strand breaks by etoposide (both agents are shown in yellow) can block proliferation of leukemia. In general, inaccuracies of the DNA damage response allows accumulation of oncogenic mutations which favors the clonal outgrowth of genetically unstable clones to enhance leukemic progression. Proteins that are frequently overexpressed or mutated and hence contribute to leukemic transformation are marked in red. Tumor suppressor proteins are marked in green. Therapeutics is marked in yellow. See text for details.