Role of ARHGAP21 in the medullary stroma, maintenance of hematopoiesis in vitro and in the CXCL12/CXCR4 signaling pathway in vivo

• Grant number: 16/14276-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2016
• End date: August 31, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Sara Teresinha Olalla Saad
• Grantee: Aline Lisie Ramos
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 11/51959-0 - Biology of neoplastic diseases of bone marrow, AP.TEM

Abstract

The bone marrow (BM) is composed by specific microenvironments: the osteoblastic niche, which is responsible for the maintenance of quiescent primitive hematopoietic stem cells, and vascular niche which maintains progenitor and stem cells proliferating and ready to begin the differentiation process. CXCL12 is an important chemo active factor produced by the BM cells; the action of this factor upon the CXCR4 receptor, expressed by hematopoietic cells, plays a key role in migration, homing and development of hematopoietic progenitor cells in BM. Myeloid and lymphoid leukemic cells express CXCR4 and thereby reach protected sites of the BM, where they secrete cytokines cells which sequester healthy haematopoietic precursors to the atypical MB niches, impairing their maintenance. Considering the unbalance ofthe CXCL12/CXCR4 signaling pathway in leukemia, it is essential to search for new therapeutic targets involved in this pathway. In this sense, our group have identified a human gene highly expressed in peripheral blood leukocytes from leukemic patients,which encodes for RHGAP21 protein, that interacts with FAK and PKCz kinases involved in CXCL12 signaling pathway. Furthermore, ARHGAP21 silencing in leukemic myeloid cells induce to cell death. These data suggest that ARHGAP21 is an interesting subject of study in CXCL12/CXCR4 signaling for better understanding of the bone marrow phenomenon related with leukemia progress. Therefore, in this project we propose to investigate the role of ARHGAP21 in the bone marrow stroma and in normal and neoplastic hematopoiesis maintenance. (AU)