The clinical course of chronic lymphocytic leukemia (CLL) is highly variable; hence, an appropriate treatment protocol is essential. Chemotherapy drugs, for example fludarabine, exert anti-tumor functions dependent on the normal function of p53. CLL patients with del(17p13) have a poor response to the present regimes, and there is no standard treatment. Therefore, p53 status is associated with the appropriate treatment protocols for CLL patients.
The tumor suppressor p53 plays a central role in the regulation of cell cycle, apoptosis, DNA repair and senescence.[3-7] Once the p53 gene is inhibited or inactivated, it promotes tumor development. Distinct pathways have been identified that cause p53 activation, and ataxia telangiectasia mutated (ATM)-dependent response to DNA damage is one of them. ATM kinase as a key molecule activates p53 after DNA damage. There are several regulators taking part in p53 activation, such as murine double minute 2 (MDM2) and murine double minute 4 (MDM4). After DNA damage, phosphorylation of full-length MDM4 (FL-MDM4), in an ATM-dependent manner, increases binding, ubiquitination and degradation of MDM2, and eliminates its inhibition on p53.
The purpose of this study was to investigate the prognostic significance of MDM4, and to characterize the role of MDM4 in the p53 pathway. We detected the expressions of FL-MDM4, a splicing variant of MDM4 (S-MDM4) and MDM2 mRNA by quantitative PCR (qPCR) in 140 Chinese CLL patients, and analyzed the correlation between those murine double minute (MDM) expressions and CLL prognostic markers. Furthermore, primary CLL cells were treated in vitro with either fludarabine or Nutlin-3, to explore the interaction between p53 status and the MDM.