Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute Leukemia

Abstract

Acute leukemias are aggressive hematological malignancies characterized by clonal proliferation with replacement and accumulation of neoplastic cells in the bone marrow, peripheral blood and other organs that suppress normal hematopoiesis. Despite the great advances in understanding the complexity involved in the molecular changes of acute leukemia in recent years, very little has been translated into novel therapies. Major investments have been made in the generation of large-scale genomic data, including public deposition of mutational profile and gene expression data in patients with hematological malignancies, a unique tool for generating and testing hypotheses based on differential expression or prognostic impact of genes. Cell cytoskeleton is an attractive therapeutic target, as this structure regulates vital cell functions and has been used as target for decades in oncology. However, the low selectivity to cancer cells of this class of drugs results in serious adverse effects. Our research group has sought to identify genes/proteins related to the regulation of actin fibers, microtubules and intermediate filaments selectively expressed or activated in leukemia cells to serve as targets for pharmacological intervention. The objectives of this project are (i) to identify cellular cytoskeleton regulatory genes, whose differential expression predicts clinical outcome in patients with acute leukemia; (ii) verify the impact of inhibition (pharmacological and/or genetic) of the selected genes on viability, proliferation, clonogenicity, apoptosis and modulation in signaling pathways in in vitro and in vivo acute leukemia models. Our expectation is to generate proof-of-concept for the identification of new targets and the development of cell cytoskeletal selective treatments for cancer cells. (AU)