Functional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia

The chemokine stromal cell-derived factor-1 (SDF-1) that is released by bon e marrow (BM) stromal cells and contributes to stem cell homing may also pl ay a role in the trafficking of leukaemic cells. We analysed SDF-1-induced intracellular calcium fluxes in leukaemic blasts from the peripheral blood of patients with newly diagnosed acute myeloid leukaemia (AML) and lymphobl astic leukaemia (B-lineage ALL), determined the effect of BM stromal cell-c onditioned medium on in vitro transendothelial migration (TM) and measured expression of the SDF-1 receptor, CXCR4, by flow cytometry. AML FAB M1/2 bl asts did not show calcium fluxes and TM was not stimulated. In myelomonocyt ic AML (M4/5), however, SDF-1 induced significant calcium fluxes and TM was increased twofold by the conditioned medium. M3 and M4 blasts with eosinop hilia (M4eo) showed intermediate activity and M6 blasts showed no functiona l activity. In ALL, strong calcium fluxes and increased TM (2.5-fold) were observed. Accordingly, expression of CXCR4 was low in undifferentiated (MO) AML, myeloid (M1/2) AML and erythroid (M6) AML, but high [mean fluorescenc e (MF) > 50] in promyelocytic (M3) AML, myelomonocytic (M4/5) AMT, and B-li neage ALL. We conclude that, in AML, SDF-1 is preferentially active in myel omonocytic blasts as a result of differentiation-related expression of CXCR 4, Functional activity of SDF-1 and high expression of CXCR4 in B-lineage A LL is in accordance with the previously described activity of SDF-1 in earl y B cells. SDF-1 may contribute to leukaemic marrow infiltration, as sugges ted by increased CXCR4 expression and migratory response in BM-derived blas ts compared with circulating cells.