A novel role of the CX3CR1/CX3CL1 system in the cross-talk between chronic lymphocytic leukemia cells and tumor microenvironment.

Several chemokines/chemokine receptors such as CCR7, CXCR4 and CXCR5 attract chronic lymphocytic leukemia (CLL) cells to specific microenvironments. Here we have investigated whether the CX₃CR1/CX₃CL1 axis is involved in the interaction of CLL with their microenvironment. CLL cells from 52 patients expressed surface CX₃CR1 and CX₃CL1 and released constitutively soluble CX₃CL1. One third of these were attracted in vitro by soluble CX₃CL1. CX₃CL1-induced phosphorylation of PI3K, Erk1/2, p38, Akt and Src was involved in induction of CLL chemotaxis. Leukemic B cells upregulated CXCR4 upon incubation with CX₃CL1 and this was paralleled by increased chemotaxis to CXCL12. Akt phosphorylation was involved in CX₃CL1-induced upregulation of CXCR4 on CLL. In proliferation centers from CLL lymph node and bone marrow, CX₃CL1 was expressed by CLL cells whereas CX₃CR1 was detected in CLL and stromal cells. Nurselike cells (NLCs) generated from CLL patient blood co-expressed surface CX₃CR1 and CX₃CL1, but did not secrete soluble CX₃CL1. Only half of NLC cell fractions were attracted in vitro by CX₃CL1. In conclusion, the CX₃CR1/CX₃CL1 system may contribute to interactions between CLL cells and tumor microenvironment by increasing CXCL12-mediated attraction of leukemic cells to NLC and promoting directly adhesion of CLL cells to NLC. [ABSTRACT FROM AUTHOR]