Proposed mechanism of actions for 5-azaC in AML. 5-azaC is majorly phosphorylated to 5-aza–CTP and incorporated into RNA. A fraction of the 5-azaC intermediate product 5-aza–CDP is converted to 5-aza–dCDP by RR, followed by further phosphorylation to 5-azaC–dCTP, which is believed to incorporate into DNA. The results of the present study identify RRM2 as a novel target of 5-azaC. The underlying molecular mechanisms for the inhibitory effects of 5-azaC on RRM2 involve its RNA incorporation and attenuated RRM2 mRNA stability.