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Detection of TP73 gene transcripts in Acute Promyelocytic Leukemia and their impact in prognosis and therapeutics response

Grant number: 17/08430-5
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): August 01, 2017
Effective date (End): March 31, 2021
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Eduardo Magalhães Rego
Grantee:César Alexander Ortiz Rojas
Home Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil

Abstract

Acute Promyelocityc Leukemia (APL) is a hematological neoplasia characterized in 95% of cases by the translocation between the chromosomes 15 and 17, resulting in the fusion of Promyelocityc Leukemia Protein (PML) gene and retinoic acid receptor ± (RAR±) gene. The PML-RARa gene is translated in a chimeric protein that prevents granulocytic differentiation. Nowadays, APL is treated with ATRA (all trans retinoic acid), a target therapy that permit the maturation of promyelocytes to granulocytes; however, some patients relapse or never responds to this treatment. Because of this, some biomarkers are being studied to find their role in APL pathogenesis and their impact on prognosis and treatment response. In this context, TP73 gene is a promising prognostic and predictive marker in APL. Our laboratory has demonstrated that Np73 expression, variant of TP73, is related to poor prognosis, but there are not studies about the impact of others variants neither their relevance on treatment. Here we aim to explore APL patients samples to determine what TP73 variants are differentially expressed in APL, and then develop an APL animal model to explore the prognostic and predictive value of these TP73 variants. This animal model will express PML-RARa gene and TP73 differentially expressed variants tested in sample patients. We will get that infecting hCG-PML/RAR± transgenic mice bone marrow cells with lentivirus system recombined with a TP73 differentially expressed variant. In these mice we will analyze the evolution of disease by testing of hemogram, immunophenotype, PML-RARa transcripts levels, TP73 variants expression, overall survival, disease free survival and other aspects in the APL animal model developed. Also, we will evaluate the success of therapy with ATRA in this animal model, using the same tests mentioned before and also the events of relapse. Finally, we will study the gene expression of some TP73 axis genes to intent explain what of the TP73 functions are relevant in the progress of APL disease. The results of this study will allow us to approach the knowledge of the impact of TP73 gene on prognosis and treatment response in APL, and what TP73 variants are relevant in this context. (AU)