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Detection and functional analysis of tumor associated macrophages in acute promyelocytic mouse model

Grant number: 17/25358-6
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): June 01, 2018
Effective date (End): May 31, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Eduardo Magalhães Rego
Grantee:Isabel Weinhauser
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 of Groningen, Netherlands  
Associated to the scholarship:15/09228-0 - Detection and functional analysis of tumor-associated macrophages (TAM) in a transgenic model of Acute Promyelocytic Leukemia (APL), BP.DR

Abstract

Tumor associated macrophages (TAM) are macrophages that were originally classified as M2 macrophages found in solid tumors working in favour of cancerogenic cells to proliferate, migrate and remain undetected to the host immune system. Since TAM were so far mainly studied in solid tumors, we were eager to investigate if TAM could as well exist and contribute to the formation of Acute myeloid leukemia (AML). More specifically we chose to study the presence and function of TAM in Acute Promyelocytic Leukemia (APL), which is a well definded AML subtype with a favorable prognosis. So far we were able to determine the presence of TAM in APL bone marrow (BM) samples from patients and observe via human and murine in vitro experiments that the co-culutre of healthy human peripheral blood monocytes and murine BM macrophages with APL blast cells induced the expression of M2 markers. Based on our current in vitro results, we intend to study the function of TAM cells and its impact on APL development in vivo. However up until now xenotransplantion with primary APL cells, has been difficult due to the lack of engraftment. For this reason we chose to perform our in vivo experiments in a humanized xenograft mouse model (available at the University of Groningen), whereby we expect to increase the probability of APL engraftment since this mouse model aims to reproduce the human BM. Hence as a first step we will test the engrafment capacity of primary APL cells in the humanized xenograft mouse model. Secondly we plan to transplant primary APL blast cells into the humanized xenograft mouse model in conjuction with the different macrophage subtypes (M0, M1 and M2) in order to observe how the different macrophage subtypes can influence the engraftment and formation of APL. Furthermore we plan to study sorted CD163+/CD206+ macrophages from APL patients compared to healthy donors on a transcriptomic and functional level and finally we will investigate the effect of ATRA on the macrophage profile.