Characterization of subpopulations of cytotoxic cells in murine models of myeloid leukemia

• Grant number: 23/01821-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2023
• End date: August 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Lorena Lôbo de Figueiredo Pontes
• Grantee: Mariana Medeiros
• Host 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
• Associated research grant: 21/06841-3 - Molecular and phenotypical mechanisms driving immune evasion in myeloid malignancies, AP.JP2
• Associated scholarship(s): 25/03925-2 - INVESTIGATION OF THE ROLE OF IMMUNE DYSFUNCTION IN MYELOFIBROSIS PROGRESSION, BE.EP.DR

Abstract

Myeloid neoplasms are diseases that begin by transforming a hematopoietic stem cell through directed mutations (or drivers). They can be classified as myelodysplastic neoplasm (MDS), myeloproliferative neoplasms (MPNs), which include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMP), and acute myeloid leukemia (AML) which may be primary (or de novo) or resulting from the evolution of the other conditions. However, these mutations are not the only events important for leukemogenesis. Extrinsic factors such as the tumor microenvironment favor the establishment of the disease and its promotion, in addition to impairing normal hematopoiesis. Among the cells that form the microenvironment are immune system cells, such as NK and T cells. NK cells have already been shown to modify the functions of stem cells, including self-renewal, and in cases of AML, these cells are immature, which can lead to the spread of leukemia. Thus, the project aims to identify molecular mechanisms involved in the cytotoxicity of NK cells and T lymphocytes in myeloid neoplasms. For this, chimeric mouse models of AML (AML1-Eto9a), CML (SCL-tTa/BCR-ABL), and NMP (Jak2V617F) will be used. After the establishment of myeloid leukemia models, spleen and marrow samples will be collected to characterize the profile of NK and T cells in these models through immunophenotyping by flow cytometry and analysis of the transcriptional profile through scRNA-seq. In this way, it is expected to identify molecular pathways involved in the performance of NK and T cells in murine models of myeloid leukemias and involved in their activation and maturation deficiency to improve immunotherapy in myeloid leukemias in the future.