S‐MDM4 mRNA overexpression indicates a poor prognosis and marks a potential therapeutic target in chronic lymphocytic leukemia

The purpose of the present study was to investigate the prognostic significance of murine double minute 4 ( MDM4 ) in chronic lymphocytic leukemia ( CLL ) and to characterize the role of MDM4 in the p53 pathway. Full‐length MDM4 ( FL‐MDM4 ), a splicing variant of MDM4 ( S‐MDM4 ) and murine double minute 2 ( MDM2 ) mRNA expressions were detected by quantitative PCR in 140 C hinese patients with CLL , and primary CLL cells were treated in vitro with either fludarabine or N utlin‐3 to explore the interaction between p53 status and MDM4 or MDM2 expression. A marked increase of FL‐MDM4 and S‐MDM4 expressions were observed in the CLL patients with p53 aberrations (deletion and/or mutation) ( P  = 0.024, P  < 0.001). A high level of S‐MDM4 mRNA expression was associated with short treatment free survival ( TFS ) ( P  = 0.004). FL‐MDM4 expression was significantly decreased after fludarabine treatment ( P  = 0.001) but increased after N utlin‐3 treatment ( P  = 0.008) of primary CLL cells without p53 aberrations. Both S‐MDM4 and MDM2 expressions were significantly increased after fludarabine treatment of CLL cells without p53 aberrations ( P  = 0.013 and P  = 0.030). MDM2 overexpression also occurred in CLL cells with p53 wild type after N utlin‐3 treatment ( P  = 0.018). FL‐MDM4 and S‐MDM4 overexpression are indicators of p53 aberrations in CLL patients, suggesting that those patients have a poor prognosis. FL‐MDM4 inhibitory effects on p53 can be removed by MDM2 ‐p53 and saved by N utlin‐3.