Investigation of ezrin inhibitors on Rho GTPase-mediated migratory and invasive activity in acute lymphoblastic leukemia cells

Abstract

Acute leukemias are aggressive neoplasms characterized by clonal proliferation with replacement and accumulation of neoplastic cells (e20%) in the bone marrow and other organs, and when there is the involvement of lymphoblasts they are classified as acute lymphoblastic leukemia (ALL). Despite great advances in understanding the complexity involved in the molecular changes of ALL, very little has been translated into new therapies. In preliminary analyzes using large-scale genomics data deposited by TCGA (The Cancer Genomics Atlas), differential expression of EZR (which encodes the ezrin protein) was identified as a prognostic marker and initial analyzes suggest its therapeutic potential. Ezrin is a member of the ERM family and its function is to bind the actin cytoskeleton to the cell membrane and create support for signaling molecules involved in important cellular processes. Rho GTPases are well known for their roles in regulating cell migration, and also contribute to a variety of other cellular responses, and they can be activated by ezrin. The identification of new molecular markers of prognosis and signaling pathways/selective targets for pharmacological intervention is of interest in the study of acute leukemias, which may improve clinical management and generate new opportunities for therapies. The objectives of this proposal are: To determine the impact of ezrin inhibition on migration, invasion, and Rho GTPase activity using cellular models of ALL. (AU)