دورية أكاديمية
Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a
| العنوان: | Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a |
|---|---|
| المؤلفون: | Fontana, Maria Chiara, Nanni, Jacopo, Ghelli Luserna di Rorà, Andrea, Petracci, Elisabetta, Padella, Antonella, Ghetti, Martina, Ferrari, Anna, Marconi, Giovanni, Soverini, Simona, Iacobucci, Ilaria, Papayannidis, Cristina, Curti, Antonio, Audisio, Ernesta, Giannini, Maria Benedetta, Rondoni, Michela, Lanza, Francesco, Cavo, Michele, Martinelli, Giovanni, Simonetti, Giorgia |
| المساهمون: | Fontana, Maria Chiara, Nanni, Jacopo, Ghelli Luserna di Rorà, Andrea, Petracci, Elisabetta, Padella, Antonella, Ghetti, Martina, Ferrari, Anna, Marconi, Giovanni, Soverini, Simona, Iacobucci, Ilaria, Papayannidis, Cristina, Curti, Antonio, Audisio, Ernesta, Giannini, Maria Benedetta, Rondoni, Michela, Lanza, Francesco, Cavo, Michele, Martinelli, Giovanni, Simonetti, Giorgia |
| سنة النشر: | 2021 |
| المجموعة: | Università degli Studi di Ferrara: CINECA IRIS |
| مصطلحات موضوعية: | AML, novel therapeutic target, WIP1, MDM2 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | STAMPA |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/33917342; info:eu-repo/semantics/altIdentifier/wos/WOS:000642803400001; volume:9; issue:4; firstpage:388-1; lastpage:388-19; numberofpages:19; journal:BIOMEDICINES; http://hdl.handle.net/11392/2453986Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85104681514; https://www.mdpi.com/2227-9059/9/4/388/pdfTest; https://www.mdpi.com/2227-9059/9/4/388Test |
| DOI: | 10.3390/biomedicines9040388 |
| الإتاحة: | https://doi.org/10.3390/biomedicines9040388Test http://hdl.handle.net/11392/2453986Test https://www.mdpi.com/2227-9059/9/4/388/pdfTest https://www.mdpi.com/2227-9059/9/4/388Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.D2A26315 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3390/biomedicines9040388 |
|---|