CXCR7 functional investigation in normal and leukemic hematopoiesis

Author(s)

Rita de Cássia Carvalho Melo

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2016-02-06

Examining board members

Sara Teresinha Olalla Saad; Cristiane Okuda Torello; Mariana Lazarini; Claudia Bincoletto Trindade; Lorena Lobo de Figueiredo Pontes

• Advisor: Sara Teresinha Olalla Saad

Abstract

The interaction of CXCL12 chemokine to CXCR4 has been shown to be essential in the regulation of normal and leukemic hematopoiesis. Recently, another receptor for CXCL12, more commonly known as CXCR7 was discovered, however the expression and function of this receptor in hematopoietic cells is controversial. Depending on the cell type, this receptor can activate ?-arrestin2-mediated signaling pathways, form heterodimers with CXCR4 and/or remove CXCL12 from the extracellular medium, mediating degradation and preventing the CXCL12 induced-downregulation of CXCR4. In addition to studying chemokines and their receptors, it is important to study the proteins that are activated as a result of their connection, such as ARHGAP21, a protein belonging to the family RhoGAP (RhoGTPase activating proteins), whose main role is to downregulate the RhoGTPases. This protein can also trigger biological events beyond the GAP function through its interaction with other proteins. Previous studies have shown that Arhgap21+/- mice showed a reduction in migration, adhesion and homing of progenitor cells (Lin-) to hematopoietic organs and reduction in the frequency of myeloid lineage cells, T lymphoid and erythroid in bone marrow; these are important cellular processes mediated by the interaction CXCL12/CXCR4 and possibly also in CXCR7, however this has not yet been verified. The overall objective of this study was to investigate and characterize the CXCR7 function in normal hematopoiesis and acute myeloid leukemia. We show that CXCR7 is important in the migration and homing of CD34+ cells and cells of acute myeloid leukemia to hematopoietic organs. In the latter, CXCR7 can prevent the downregulation of CXCR4 caused by CXCL12. The CXCR7 gene has a lower expression in total bone marrow cells and the receptor's protein is reduced in the cell membrane of CD3+ T lymphocytes in Arhgap21+/- mice. CD3+ T lymphocytes of Arhgap21+/- mice also have a lower migration in response to CXCL12. CXCR7 reduction in the cell membrane of these cells can be caused by a problem in ?-arrestin2-recruiting, an important protein in endocytosis and in the recycling of receptors in the cell membrane, as a reduction in the process in these mice was also observed. Together, these results indicate that CXCR7 is important in the migration of normal hematopoietic cells, T lymphocytes and CD34+ cells, and cells of acute myeloid leukemia, interfering with the action of other important receptor for CXCL12, CXCR4. This interference would be to "remove" CXCL12 in order to reach a suitable gradient for the operation of CXCR4, and/or the ability to form heterodimers with this receptor modulating and potentiating the interaction of CXCL12/CXCR4 (AU)

• FAPESP's process: 12/01030-8 - Functional Investigation of CXCR7 Normal and Leukemic Hematopoiesis
• Grantee: Rita de Cássia Carvalho Melo
• Support Opportunities: Scholarships in Brazil - Doctorate