Stromal Cell Derived Factor 1 and Chemokines

Although the effects of many chemokines are largely redundant, and several chemokines can usually bind the same receptor, stromal-derived factor-1 (SDF-1) is a chemokine with the unique features of nonredundant functions (mutant mice die perinatally) and capable of binding to a single receptor, CXCR4 (154,155). SDF-1, initially designated as pre-B-cell growth-stimulating factor (PBSF), plays an important role in B-cell development, retaining B-cell precursors in close contact with bone marrow stromal cells, and it may also function as a B-cell growth factor (156,157). SDF-1 is constitutively produced by bone marrow stromal cells and acts as a chemoattractant, supporting the homing of hematopoietic cells, on which the chemokine receptor CXCR4 is broadly distributed (158,159). On circulating CLL cells, CXCR4 was found to be consistently expressed at a fluorescence intensity fourfold greater than that of normal B-cells and threefold greater than that of normal bone marrow CD19+/CD5+ cells. Migration of CLL cells was also more efficiently stimulated by recombinant SDF-1 compared with migration of normal B-cells (160). Burger et al. (161) have confirmed these findings in a study that investigated the function of CXCR4 expression on CLL cells. The critical role of the chemokine receptor CXCR4 for heterotypic adherence to marrow stromal cells was demonstrated by experiments in which CLL B-cells were cocultured with a murine cell line that secretes SDF-1: CLL B-cells spontaneously migrated beneath such stromal cells, and this migration could be inhibited by anti-CXCR4 monoclonal antibodies. In addition to this role in CLL B-cell migration, the same authors proposed in a recent paper a new role for SDF-1 in sustaining CLL leukemic cell survival. In fact, they identified a new population of stromal cells in the peripheral blood of CLL patients, named blood-derived nurse-like cells, capable of adhering to CLL B-cells in vitro and protecting them from undergoing spontaneous apoptosis. The process was SDF-1-dependent, since neutralizing antibodies to SDF-1 inhibited this protecting effect, and it could be partially mimicked, in the absence of the nurse cells, by exogenous SDF-1 (162) (Fig. 4).

At variance from the ubiquitous expression of CXCR4, the recently cloned chemokine receptor CXCR3 has been reported to be expressed on activated T-cells, but it is usually lacking in resting T-lymphocytes and most CD5+ and CD5- B-cells (163,164). This receptor is also expressed on the surface of leukemic CLL cells and is fully functional (165). In fact, malignant B-cells from patients with CLL show a definite in vitro migration in response to IFN-inducible protein 10 (IP-10) and IFN-y-induced monokine (Mig), two chemokines that bind the CXCR3 receptor. CXCR3 expression appears to be a specific marker of CLL leukemic cells, since cells from patients with other B-cell malignancies, such as mantle cell lymphoma, follicular lymphoma, and hairy cell leukemia, were found to be generally negative (165,166). The same authors report that the CXCR3 ligand, Mig, is coexpressed on the leukemic cells in many cases of CLL. Coexpression of CXCR3 and its ligand, Mig, may play an important functional role in CLL, which needs to be further investigated.

The chemokine and chemokine receptor family is growing. According to NH2-terminal cys-teine motifs, chemokines are divided into the C, CC, CXC, and CX3C subfamilies, and new members are being constantly added (167). Well-known molecules with chemotactic properties have been included in this classification and renamed following these criteria. This is the case for IL-8, now called CXCL8, whose role in sustaining CLL leukemic cell survival has already been discussed. In addition, IL-8 is capable of inducing motility of CLL cells on hyaluronan and thus is likely to be important for CLL cell migration through lymphoid tissues (168). In this context, future studies are likely to define additional factors that may have a role in mediating CLL leukemic cell trafficking and adhesion mechanisms. Assessing the relevance of these

SURVIVAL?

SURVIVAL?

MARROW BLOOD

Fig. 4. Stromal-derived factor-1 (SDF-1) and bone marrow infiltration by CLL cells. CLL lymphocytes express high levels of SDF-1 receptor CXCR4 and may be attracted in the bone marrow by stromal cell-derived SDF-1. In the peripheral blood, SDF-1 released by "nurse-like" cells might also function as a CLL cell survival factor.

MARROW BLOOD

Fig. 4. Stromal-derived factor-1 (SDF-1) and bone marrow infiltration by CLL cells. CLL lymphocytes express high levels of SDF-1 receptor CXCR4 and may be attracted in the bone marrow by stromal cell-derived SDF-1. In the peripheral blood, SDF-1 released by "nurse-like" cells might also function as a CLL cell survival factor.

processes on CLL cell survival and disease spreading might lead to new therapeutic avenues for patients with CLL.

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