Mutated and non-mutated TP53 as targets in the treatment of leukaemia

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• TP53 mutations are present in 10-20% of CLL and 3-8% of AML cases.
• Two classes of compounds, PRIMA-1 and RITA, restore p53 function in tumors.
• PRIMA-1 restores wild-type p53 conformation, while RITA increases intracellular p53 levels.

Purpose of the Study:

• To evaluate the effects of RITA, PRIMA-1, and conventional cytostatics on leukaemic cells.
• To investigate the efficacy of p53-targeting small molecules in AML and CLL.
• To explore synergistic effects of RITA in combination therapies.

Main Methods:

• Leukaemic cells from AML and CLL patients were treated with RITA and PRIMA-1.
• Drug sensitivity assays were performed comparing samples with and without specific genetic markers (e.g., -17 in AML, TP53 deletion in CLL).
• Apoptosis and cytotoxicity were measured to assess treatment efficacy.

Main Results:

• PRIMA-1 effectively killed AML samples with -17, which are typically daunorubicin/cytarabine resistant.
• RITA induced apoptosis in AML cells, with higher sensitivity in samples lacking -17.
• RITA demonstrated dose-dependent apoptosis and cytotoxicity in CLL cells, particularly those without hemizygous TP53 deletion.
• A synergistic effect was observed between RITA and fludarabine in all CLL samples.
• RITA exposure increased intracellular p53 levels in both AML and CLL cells.

Conclusions:

• Small molecules targeting p53, such as RITA and PRIMA-1, show potential for treating leukaemic cells.
• These compounds may be clinically important for future treatment of drug-resistant leukaemias.
• RITA's ability to induce apoptosis and synergize with existing therapies highlights its therapeutic potential.