MDMX/MDM4 is highly expressed and contributes to cell growth and survival in anaplastic large cell lymphoma

Abstract

We hypothesized that murine double minute X (MDMX), a negative p53-regulator, may be involved in dysfunctional p53-signaling in anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive and ALK-negative, characterized frequently by non-mutated TP53 (wt-p53). By western blot analysis, MDMX was highly expressed in ALK + ALCL and expressed at variable levels in ALK- ALCL cell lines. By immunohistochemistry, high MDMX levels were observed more frequently in ALK + ALCL (36/46; 78%), compared with ALK- ALCL tumors (12/29; 41%) (p < .0018, Mann–Whitney-test). FISH analysis showed MDMX-amplification in 1 of 13 (8%) ALK- ALCL tumors, and low-level MDMX copy gains in 2 of 13 (15%) ALK- ALCL and 3 of 11 (27%) ALK + ALCL tumors. MDMX-pharmacologic inhibition or siRNA-mediated MDMX-silencing were associated with activated p53 signaling, growth inhibition and apoptotic cell death in wt-p53 ALCL cells, providing evidence that targeting MDMX may provide a new therapeutic approach for ALCL patients with wt-p53.

Keywords:

• non-Hodgkin
• lymphoma
• anaplastic
• MDMX
• p53
• ALK

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This study has been partially supported by European Union and Greek national funds (KA 3499, 3703 and 10071) (to ED). It was also supported by grants from Radiumhemmets Forskningsfonder (project 174243), Cancerfonden (19 0277 Pj), Barncancerfonden (PR2019-0133) (to GZR), European Commission and Ministry of National Education and Religious Affairs.