Evaluation of the cellular and molecular effects of pharmacological AURKA and AURKB inhibitors in Ba/F3 cells carrying the CSF3RT6181 mutation

• Grant number: 22/11039-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2022
• End date: July 31, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Natália Sudan Parducci
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Myeloproliferative neoplasms (MPN) are consolidated as a relevant group of diseases derived from the malfunction of the hematopoiesis process and have as a particular attribute the increased proliferation of one or more myeloid series. Among these, chronic neutrophilic leukemias (CNL) are distinguished, recognized in the form of BCR::ABL1 negative MPN and identified through a variety of diagnoses, recently improved with the use of biomarkers. In the case of CNL, one of these biomarkers is the T618I mutation of the CSF3R gene. This gene acquires the function of inducing the proliferation and differentiation of neutrophils in addition to promoting the mobilization of hematopoietic progenitor cells from the bone marrow to the blood. The T618I mutation generates ligand-independent receptor activation and downstream signaling through JAK2. Other works with the IL3-dependent lymphocytic lineage, Ba/F3, showed that mutations in BCR::ABL1 and JAK2V617F increased the expression of aurora kinase (AURK) family proteins, more specifically AURKA and AURKB. Preclinical studies have illustrated the efficacy of pharmacological inhibitors of AURKs as antineoplastics, such as the drugs aurora A inhibitor I, AZD1152-HQPA and reversine. Delimited the current scenario, the aim of this study is to verify the participation of AURKA and AURKB in the proliferation of the disease and to evaluate the cellular and molecular effects of their pharmacological inhibitors in a cell model with CSF3RT618I mutation.