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APR-246 (Eprenetapopt) is a small-molecule drug that restores the activity of dysfunctional p53 proteins caused by missense mutations that affect the DNA-binding domain. However, recent studies suggest that APR-246 can also induce cell death in cancer cells that carry wild-type (WT) TP53. Here, we aimed to determine the impact of APR-246 on the survival of acute myeloid leukemia (AML) cells using isogenic Molm13 cells that harbor WT TP53, a missense mutation of TP53R175H, or a biallelic deletion of TP53 (TP53−/−). Our results showed that Molm13 TP53−/− cells were significantly more resistant to APR-246-induced cell death compared with their Molm13 TP53R175H/− mutant and Molm13 TP53+/+ counterparts. In addition, knockdown of TP53 significantly reduced cytotoxicity induced by APR-246 in two TP53 WT AML cell lines (MV4-11 and OCI-AML2). Moreover, APR-246 markedly decreased the clonogenicity of TP53 WT hematopoietic stem/progenitor cells (HSPCs) isolated from humans and mice. In contrast, biallelic loss of TP53, but not TP53 missense mutation, significantly increased the resistance of mouse HSPCs to APR-246. Mechanistically, the loss of functional p53 proteins in Molm13 and MV4-11 cells decreased intrinsic apoptosis and impaired the production of cellular reactive oxygen species (ROS) induced by APR-246. Together, our results indicate that, in at least a subset of AML cell lines and normal HSPCs, APR-246-induced ROS production and cytotoxicity are enhanced in the presence of WT p53 proteins.
Cart et al. (Sat,) studied this question.