A Splicing Variant of MDM4 Overexpression Plays an Indicator of p53 Aberrations and Marks a Potential Therapeutic Target in Chronic Lymphocytic Leukemia

Human homolog of murine double minute 4 (MDM4) belongs to murine double minute (MDM) family. Splicing variant of MDM4 (S-MDM4) is obtained from the deletion of exon 6, which results in an internal deletion of 68 bp. Murine double minute 2 (MDM2) is an analogy of MDM4 and shares highly similar structure with each other. The MDM4 gene plays a crucial role in regulating p53 activity and has been found to overexpress in chronic lymphocytic leukemia (CLL). The purpose of this study was to investigate the prognostic significance of MDM4, and characterize the role of MDM4 in p53 pathway.

Full-length MDM4 (FL-MDM4), S-MDM4 and MDM2 mRNA expressions were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in 140 Chinese patients with CLL. The correlation between those MDM expressions and CLL prognostic marker such as clinical stage, immunoglobulin heavy-chain variable region (IGHV) mutational status, ZAP-70, CD38, and chromosomal abnormalities were analyzed. Furthermore, primary CLL cells were treated in vitro with either fludarabine or Nutlin-3, to explore the interaction between p53 status and those MDMs.

FL-MDM4 and S-MDM4 expressions were significantly increased with the del(17p13) (P=0.037 and P=0.006), p53 mutations (P=0.023 and P<0.001) and p53 aberrations (P=0.024 and P<0.001). The correlation between the level of MDM2 expression and p53 status was not observed (P=0.196, P=0.095 and P=0.092, respectively). 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 24 h treatment with fludarabine (P=0.001), but increased after Nutlin-3-treated (P=0.008) in primary CLL cells without p53 aberrations. Both S-MDM4 and MDM2 expressions were significantly increased after fludarabine-treated in CLL cells without p53 aberrations (P=0.013 and P=0.030). Besides, MDM2 overexpression also occurred in CLL cells with p53 wild type after Nutlin-3-treated (P=0.018). In the primary CLL cells with p53 aberrations or p53 dysfunction, the levels of FL-MDM4, S-MDM4 and MDM2 expressions were not significantly increased or decreased after fludarabine or Nutlin-3 treatment.

S-MDM4 overexpression is an indicator of p53 aberrations in CLL patients, suggesting those patients have a poor prognosis. FL-MDM4 inhibitory effect on p53 can be removed by MDM2-p53 and saved by Nutlin-3, and S-MDM4 overexpression marks a potential therapeutic target in CLL.

No relevant conflicts of interest to declare.