Fibronectin increases the migration induced by stromal cell-derived factor-1 alpha (SDF-1 alpha) in pre-B acute lymphoblastic leukemia cells

The chemokine, stromal cell-derived factor-1 alpha (SDF-1 alpha) and its re ceptor CXCR-4 (fusin, LESTR) are thought to be involved in the trafficking of hematopoietic progenitors and stem cells, as suggested by the chemotacti c effect of SDF-1 alpha on these cells. Gene inactivation studies have show n that both SDF-1 alpha and CXCR-4 are essential for B lymphopoiesis, Migra tion of leukemic cells may also be dependent on SDF-1 alpha and CXCR-4, Fib ronectin (FN) is a component of the extracellular matrix (ECM), and one of the natural supports for cell movement in their bone hematopoietic environm ent. In the present study, we examined the influence of FN on the chemotact ic effect of SDF-1 alpha and on the CXCR-4 expression and function on human precursor-B acute lymphoblastic leukemia (pre-B ALL) cells at sequential s tages of development. Fourteen children with pre-B ALL were studied. Their immunophenotypes belonged to the first three stages of B cell differentiati on. Despite relatively high levels of CXCR-4 expression at all stages, the responsiveness to SDF-1 alpha, measured as the percentage of migrating cell s in the transwell culture system, varied with patients and seems to be les s significant for pre-B3 (and pre-B1) than for pre-B2, There was no correla tion (r = 0.2) between the SDF-1 alpha induced migration (range: 2.5-39%) a nd the cell surface density of CXCR-4 (range: 46.5-97.5%). The extracellula r matrix protein FN, either coated on the filter (for more than 18 hours) o r in soluble form, enhanced the SDF-1 alpha induced migration of pre-B ALL respectively (2 fold and 1.6 fold) without influencing CXCR-4 expression in short term cultures. Therefore, we analyzed the expression of the FN recep tors, VLA-4 (CD49d) and VLA-5 (CD49e), by direct immunofluorescence, on the se leukemic cells. VLA-4 was strongly expressed in all stages of pre-B ALL (range: 77-97%) while VLA-5 expression was more variable (range: 14-94%), b ut no correlation with the FN-dependent increased SDF-1 alpha chemotactic e ffect was noted. In conclusion, the migratory behavior of pre-B leukemic ce lls in response to SDF-1 alpha partly depends upon the stage of differentia tion, and partly upon unexplained patient variability. Our results suggest that several molecules from the extracellular matrix, such as FN, may be im plicated in this phenomenon.