Functional investigation of Stathmin 1 in proliferation, differentiation and apoptosis in acute promyelocytic leukemia model

• Grant number: 19/01700-2
• Support type: Scholarships in Brazil - Master
• Effective date (Start): August 01, 2019
• Effective date (End): July 31, 2021
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Hugo Passos Vicari
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute promyelocytic leukemia (APL) is associated with t (15; 17) (q22; q21) translocation, which results in the fusion of PML and RAR± genes, generating the hybrid gene PML-RAR±. The clinical course has been modified in recent years from acute rapidly fatal leukemia to one of the most curable AML subtypes. Although uncommon, resistance to target therapy may occur and the mechanisms involved are still unclear. Since molecular pathogenesis is well established in APL, this disease becomes an interesting model for the evaluation of cellular mechanisms of the participation of proliferation and differentiation-related oncoproteins, and the knowledge generated can be transposed into orphan haematological neoplasms of specific target therapy. In this sense, our research group has shown that the Stathmin 1 gene (STMN1), a cytoplasmic phosphoprotein that acts as a destabilizing microtubule that allows greater capacity for cell cycle progression and proliferation, is highly expressed in a cohort of 121 patients with APL. Preliminary functional studies indicate that microtubule dynamics is a potential target for APL cells, including ATRA-resistant cells. The present study aims to investigate the effects of Stathmin 1 inhibition on proliferation, cell cycle progression, apoptosis, cell differentiation, microtubule dynamics and in vivo tumorigenesis of human cell lines of sensitive LPA (NB4) or resistant to ATRA (NB4-R2). (AU)