Journal
BIOMEDICINES
Volume 9, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines9040388
Keywords
AML; novel therapeutic targets; WIP1; MDM2
Categories
Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [19226]
- ERA PerMed (ERA Net Grant) [779282]
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In acute myeloid leukemia (AML), WIP1 inhibition proved to enhance the efficacy of MDM2 inhibitor Nutlin-3a in TP53-wt cases. Gene expression analyses showed increased p53, MDM2 and p21 levels in treated TP53-wt cells, while the drug combination synergistically reduced viability and induced apoptosis in TP53-wt AML cells. This study highlights the potential of targeting WIP1 to improve therapeutic outcomes in AML patients with wild-type TP53.
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.
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