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Immunophenotypic, secretory and metabolic profile of platelets in Myeloproliferative Neoplasms

Grant number: 22/13366-2
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2023
Status:Discontinued
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Fabíola Attié de Castro
Grantee:Vitor Leonardo Bassan
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Myeloproliferative neoplasms (MPN) are clonal hematological disorders resulting from genetic mutations in the hematopoietic stem cell that promote hyperproliferation and accumulation of precursor and mature myeloid cells in bone marrow and peripheral blood. The BCR-ABL1 negative MPN, in this work, are represented by Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (MF). The pathophysiology of these diseases is associated with genetic alterations involving the genes that encode Janus Kinase 2 (JAK2), calreticulin (CALR), thrombopoietin receptor (MPL) proteins and alterations in epigenetic regulators of cell proliferation, such as TET2, IDHs and DNMTs enzymes. Although dysregulated hematopoiesis in MPN is mainly attributed to genetic and epigenetic mutations in the stem cell, abnormalities in the immune system and in the cells that compose the medullary microenvironment seem to contribute to the pathophysiology of these disorders, considered as pre-leukemic oncoinflammatory diseases characterized by high levels of inflammatory markers in plasma and exacerbated inflammatory activity. The pro-inflammatory profile, therefore, favors genetic instability and increases the risk of thrombosis, hemorrhage and cardiovascular changes in patients. Studies indicate that granulocytes, monocytes and platelets participate in the prothrombotic state in MPN. Platelets have important secretory, hemostatic and pro-inflammatory functions, being considered as accessory cells of the immune response. The activities performed by platelets in the oncoinflammation process and their influence on the occurrence of thromboembolic events have not yet been elucidated in MPN. In this context, the present work intends to describe the immunophenotypic and metabolic alterations and determine the secretory function of platelets in patients with MPN. Therefore, peripheral blood platelets from patients with PV (n=20), ET (n=20), MF (n=10) and controls (n=20) will be isolated and submitted to immunophenotyping to determine the expression of markers associated with its activation status (CD41a, CD62P, CD63, CD36, CD38 and CD154), as well as the determination of the secretory profile by means of quantification of CCL2, CXCL4/PF-4, CCL5, CXCL10, CXCL2/MIP-2, IL-1±, IL-6, IL-10, IL-17/IL-17A, VEGF, IFN-³, IL-4, IL-8, IL-12/IL-23 p40 and TNF-± by Multiplex technology (Luminex® ). Furthermore, the metabolic profile of platelets will be determined by high resolution liquid chromatography coupled to mass spectrometry (HRLC-MS), in order to evaluate the global profile of bioactive lipids (eicosanoids, leukotrienes, prostaglandins, sphingolipids) in platelets. The results obtained will be correlated with the clinical and laboratory data of the patients and will help to determine the degree of activation, the metabolic profile and the secretory potential of platelets in patients with PV, ET and MF, contributing to elucidate the role of platelets in oncoinflammation and in the description of its influence on the occurrence of cardiovascular events in patients with MPN. (AU)

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