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Role of ARHGAP21 in SDF-1/CXCR4 signaling pathway in vivo and its association with the INEFICIENT hematopoiesis in myelodysplastic syndrome

Grant number: 12/14286-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): November 01, 2012
Effective date (End): October 31, 2015
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Sara Teresinha Olalla Saad
Grantee:Aline Lisie Ramos
Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Bone marrow (BM) is composed of specific microenvironments: the osteoblastic niche, which is responsible for maintaining the most primitive hematopoietic stem cells in a quiescent state, and the vascular niche that maintain the stem and progenitor cells proliferating and ready to begin the differentiation process. Stromal derived factor-1 (SDF-1) or CXCL12 is an important chemoattractive factor produced by BM cells, its action on its receptor CXCR4, expressed by hematopoietic cells, plays major role in the migration, retention and development of hematopoietic progenitors in the BM. Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, peripheral cytopenias, dysplasia and predisposition for transformation to acute myeloid leukemia (AML). Myeloid and lymphoid leukemic cells express CXCR4 and thereby affect protected sites in BM, where they secrete cytokines that sequester healthy hematopoietic precursors in anomalous BM niches, damaging its maintenance. Facing the deregulation of the SDF-1/CXCR4 signaling pathway in MDS, it is imperative to search for new therapeutic targets involved in this signaling pathway. In this respect, our group has identified the gene encoding the protein ARHGAP21 highly expressed in peripheral blood leukocytes, whose protein product interacts with the kinases FAK and PKCzeta, associated to SDF-1 signaling. Furthermore, inhibition ARHGAP21 in myeloid leukemic cells induces cell death. These data suggest that ARHGAP21 is an interesting subject of study in SDF-1/CXCR4 signaling in regard to a better understanding of the medullary phenomena related to the MDS involvement. Therefore, here we propose to investigate the role of ARHGAP21 in in vivo tumor development and evaluate the expression, activation and possible interactions between SDF-1, CXCR4, FAK, PKCzeta, MMP-2 and MMP-9 in these tumors.