Investigation of the impact of mutations in the TP53 gene on clinical outcome and the interaction of the p53 protein with the drug APR-246 in acute myeloid leukemia

• Grant number: 24/07906-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2024
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Letícia Machado Favery Bertoline
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute myeloid leukemia (AML), one of the main types of leukemia, is caused by mutations in hematopoietic stem cells located in the bone marrow, peripheral blood and/or other tissues. Over the years, many therapeutic approaches have been developed, such as chemotherapy, hematopoietic stem cell transplantation and target therapy, which came about with the advent of studies that made it possible to associate genes with phenotype. Once the proteins encoded by these genes have been studied, it is possible to develop therapies that restore the correct functioning of the cellular machinery, such as p53, which when mutated in AML generates a very unfavorable prognosis. The gene that encodes it, TP53, is one of the most common genes associated with cancer, which is why it has been widely studied. Among the compounds developed to reactivate p53, APR-246 has shown promising results. The aim of this study is to investigate the relationship between TP53 mutations, clinical outcomes and clinical-laboratory associations, as well as to understand how different mutations can modulate the interaction between p53 and the APR-246 compound.To this end, two cohorts of AML will initially be analyzed. Subsequently, computational studies will allow us to determine the structure and mutations to be used in docking tests and molecular dynamics simulations to assess the interaction of the compound with the protein. Next, we will evaluate the effects of APR-246 under specific mutations in TP53, in relation to proliferation, apoptosis, autophagy, cell cycle progression in the presence of chemotherapeutic agents for clinical use in experimental models of AML.