Despite massive advances in the treatment of paediatric acute lymphoblastic leukaemia (ALL) challenges remain. Disease in the central nervous system (CNS) continues to pose difficulties in diagnosis, prevention and treatment. Understanding the biological mechanisms of leukaemic cell entry into the CNS should allow better detection and monitoring of leukemia and may identify novel therapeutic targets for resistant disease. We hypothesize that leukaemic cell dissemination to the CNS is associated with the abnormal expression of molecules governing physiological leukocyte trafficking i.e. chemokine receptors, selectins and integrins. This study compared gene, protein and functional expression of candidate trafficking molecules expressed by CNS homing and CNS non-homing ALL cell lines in vitro. Initial screening for candidate gene expression was performed using Taqman low density quanti- tative PCR arrays. Promising candidates were further evaluated by flow cytometry and functional assays. Clear differences were seen between the cell lines. CNS homing cells expressed higher levels of chemokine receptors, integrins and selectins associated with physiological entry of leukocytes across the blood:CSF barrier. In contrast, CNS homing cells showed much lower levels of CXCR4 expression, with reduced chemotaxis in response to the CXCR4 ligand CXCL12. Since functional CXCR4-CXCL12 interactions are known to be important for retention of cells in the bone marrow microenvironment, disruption of this interaction may be a necessary pre-requisite for cell migration to other sites. In conclusion, these studies support our hypothesis that the ability of leukemic cells to enter the CNS is governed by the expression patterns of leukocyte trafficking receptors.
- central nervous system
- paediatric acute lymphoblastic leukaemia
- leukaemic cells