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Evaluation of the TP53/TP73 pathway in the engraftment of primary Acute Promyelocytic Leukemia cells using a xenotransplantation model

Grant number: 19/14057-0
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): November 06, 2019
Effective date (End): November 05, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Eduardo Magalhães Rego
Grantee:Diego Antonio Pereira Martins
Supervisor abroad: Jan Jacob Schuringa
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : University Medical Center Groningen (UMCG), Netherlands  
Associated to the scholarship:17/23117-1 - Evaluation of TP53/TP73 pathway in engraftment of Acute Promyelocytic Leukemia cells in xenotransplantation model, BP.DR

Abstract

Current murine xenotransplantation models used as in vivo study models of human leukemic processes have failed to reconstruct disease-related pathophysiological processes due to non-similarity to the human bone marrow niche. Thus, the evaluation of the high-renewal, differentiation and transformation processes of human hematopoietic stem cells (HSCs) and leukemic (LSCs), as well as their evaluation as to the efficacy of new treatment modalities, should be performed in species-specific microenvironment. This is supported by the fact that some leukemic subtypes (grouped in the favorable prognosis group), such as human acute promyelocytic leukemia (APL), present a recurrent graft failure in xenotransplantation models, and despite its favorable prognosis compared to other acute leukemias, these subtypes still present high mortality rates and risk of relapse. In this sense, it is believed that genetic variations that confer greater resistance to the leukemic clone can influence the engraftment capacity of these cells, favoring their in vivo evaluation. Previous studies from our group have shown that a higher expression ratio ”Np73/TAp73 is associated with poorer prognosis in APL (reduced overall survival and disease-free survival) and resistance to cytarabine-induced apoptosis. The ”Np73, a truncated form of the TP73 gene, acts as a potent inhibitor of the transcriptional activity of TP53 and TAp73 proteins, thus playing an important role in cell proliferation and viability. Thus, the oncogenic activity of the TP73 gene is determined by the balance between its transcriptionally active (TAp73) and inactive isoforms (”Np73), and this relationship correlates with clinical prognosis and treatment failure in several human malignancies. Thus, the present work aims to determine if alterations in the TP53/TP73 pathway are associated with increased engraftment capacity in induced CD34+ cells and in samples from APL patients in humanized xenotransplantation models. Underlying this, we will investigate the mechanisms by which the TP53/TP73 pathway may confer PML-RAR±+ cells advantages of engraftment, leaded by increased cell proliferation, viability, cell cycle, and clonogenic capacity, associated with reduced apoptosis rate. In addition, we will evaluate the transcriptome of patients with APL who obtained and who failed to engraft in xenotransplantation models, in order to identify possible targets for the regulation of TP53/TP73. Expression of TP53/T73 pathway targets will be investigated by real-time PCR and Western blotting.