Abstract
Myelodysplastic syndromes (MDS) are a group of heterogenous hematopoietic disorders characterized by inefficient hematopoiesis. Little is known regarding MDS patogenesis and the processes that mediate their frequent transformation into leukemias. During the last years it has become evident that composition and for function alterations of the cellular microenvironment may be implicated in the progression of several hematological disorders, mainly MDS. New therapies have been proposed based on the biological characteristics of this type of tumor, however the molecular events responsible for the maintenance and dissemination of the anomalous clonal population remain unknown, frequently leading to the use of therapeutic agents that are not target specific. Therefore, the characterization of important molecular targets for differentiation processes and myeloid tumor progress could provide information, which would contribute for the creation of new drugs with greater and better action specifics. During the Human Genome Project, severaI novel genes were identified, many of which presented great potential for therapeutic targets. This project proposes to characterize the regulation of novel gene expressions, specifically ARHGAP10, MASK, and Formin, as well as other proteins, in myelodysplasias, submitted to different treatments, with the purpose of investigating molecular mechanisms of this type of tumor and the creation of new strategies for anti-tumoral therapy. Due to the nonexistence of cell or animal models with myelodysplasia, in order to fulfill some of the aims, we will use leukemia lineages as models. Furthermore mutations will be searched in genes that can associate evolving to leukemias such as PTPN11, FLT3, AML-1, GATA-1. (AU)