Influence of High Expression of p73 and p53 Proteins on Clinical Outcome in Acute Myeloid Leukemia Patients.

Background: Prognostic significance of apoptosis-regulating proteins, especially p73, is not clearly determined in acute myeloid leukemia (AML). The p73 protein is a member of p53 family implicated in the regulation of cell cycle, apoptosis and development. Overexpression of p73 protein, with prevalence of short TAp73 isoforms, has recently been described in patients with AML.

Aims: The main objective of this study was to verify whether expression of p73 and p53 proteins has a prognostic impact on response to induction chemotherapy and overall survival (OS) of adult patients with AML. Additionally, we aimed to correlate the expression of p73 and p53 proteins with spontaneous apoptosis of leukemic cells.

Material and Methods: Intracellular expression of p73 protein in leukemic blasts isolated from bone marrow or peripheral blood was examined in 73 AML patients (59 de novo, 14 refractory/relapsed) of median age 54 years (range 28–78 years). In parallel, analysis of cell cycle in leukemic blasts was performed to assess the subG1 fraction as a marker of spontaneous apoptosis. The control constituted leukemic cells incubated with isotype antibodies. All measurements were performed using multi-colour flow cytometry. Protein expression was expressed by both percentage of positive cells and mean fluorescence intensity.

Results: Fifty six patients received intensive induction chemotherapy. Twenty four (43%) patients achieved complete response (CR), 26 (46%) patients did not respond and 6 (11%) patients died in the early post-induction period. The median time of follow up reached 5.6 months (range 0.1–99 months). High expression of p73 showed a trend towards probability of CR achievement after induction regimen (p=0.08). Higher expression of p53 did not correlate with response to the treatment (p=0.28). In univariate analysis we found significantly better OS in patients less than 60 years old, with good or intermediate risk of kariotype and treated with intensive chemotherapy (p=0.00001; p=0.04; p=0.00001, respectively). Probability of better OS in AML patients with high p73 and p53 protein expression was p=0.1 and p=0.95, respectively. Simultaneous high expression of both p73 and p53 proteins on AML cell showed a trend toward longer OS (p=0.09). Moreover, a strong trend to better OS was observed in patients with high subG1 fraction. Importantly, high subG1 fraction correlated with high expression of p53 but not with p73 protein expression (p=0.03; p=0.15, respectively).

Conclusions: These data indicate that p73 protein may be implicated in apoptosis of AML in response to chemotherapy, especially when p53 pathway is abrogated. Further studies are needed to establish exact role of p73 and p53 proteins in this process and its influence on OS of AML patients.