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In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from  PPM1D , is a negative regulator of p53. We evaluated  PPM1D  expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in AML cell lines and primary samples.  PPM1D  transcript levels were higher in young patients compared with older ones and in core-binding-factor AML compared with other cytogenetic subgroups. In contrast, its expression was reduced in  NPM1 -mutated (mut, irrespective of  FLT3 -ITD status) or  TP53 -mut cases compared with wild-type (wt) ones. Either Nut-3a, and moderately WIP1i, as single agent decreased cell viability of  TP53 -wt cells (MV-4-11, MOLM-13, OCI-AML3) in a time/dosage-dependent manner, but not of  TP53 -mut cells (HEL, KASUMI-1, NOMO-1). The drug combination synergistically reduced viability and induced apoptosis in  TP53 -wt AML cell line and primary cells, but not in  TP53 -mut cells. Gene expression and immunoblotting analyses showed increased p53, MDM2 and p21 levels in treated  TP53 -wt cells and highlighted the enrichment of MYC, PI3K-AKT-mTOR and inflammation-related signatures upon WIP1i, Nut-3a and their combination, respectively, in the MV-4-11  TP53 -wt model. This study demonstrated that WIP1 is a promising therapeutic target to enhance Nut-3a efficacy in  TP53 -wt AML.

Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a