Evaluation of the effect of CEBPA inhibition on the expression of TP73 gene isoforms and its consequences in the therapy of acute myeloid leukemia

• Grant number: 23/17792-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2024
• End date: February 29, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Eduardo Magalhães Rego
• Grantee: Maria Luiza Salustiano Bandeira
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Described as the first homologue of the classic tumor suppressor gene TP53, the TP73 gene is frequently found to be overexpressed in a range of human cancers, including hematological malignancies. What characterizes its oncogenic role is the critical balance between the antagonistic activities of its isoforms: TAp73, functionally like the protein produced by TP53, and its antiapoptotic isoform Np73, which does not have the transactivation domain, but preserves its ability to bind to DNA. Previous studies indicate that patients with a higher Np73/TAp73 expression ratio are associated with worse overall survival and disease-free survival in acute myeloid leukemia (AML), possibly because they have a lower response to standard therapy. Our group demonstrated that the expression of TP73 isoforms can be controlled by the myeloid transcription factor CEBPA. Thus, the present study aims to identify the role of different isoforms of the TP73 gene in the therapeutic response using (a) murine model of AML knockout for CEBPA, (b) murine model of AML with pharmacological inhibition of CEBPA, and (c) xenotransplantation model induced by primary cells from patients containing mutations in the CEBPA gene. The murine models will be subjected to the main therapeutic protocols used in patients with AML (cytarabine + daunorubicin or protocols based on the use of Venetoclax) and the treated cells will be subjected to subsequent transcriptomic analysis to identify the molecular program of the leukemic cells.