Characterisation of the differential response of normal and CML haemopoietic progenitor cells to macrophage inflammatory protein-1 alpha

The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal haem opoietic colony forming cells (CFC), are resistant to the growth inhibitory effects of the chemokine, macrophage inflammatory protein-1 alpha (MIP-1 a lpha). Here, we tested the hypothesis that MIP-1 alpha protects normal, but not CML, CFC from the cytotoxic effects of the cell-cycle active drug cyto sine arabinoside (Ara-C). Using a 24-h Ara-C protection assay we showed tha t MIP-la: confers protection to normal CFC but also sensitises CML CFC to A ra-C. The differential MIP-1 alpha responsiveness was not due to a down-reg ulation of MIP-1 alpha receptors on CML CD34(+) cells as flow cytometric an alysis showed similar binding of a biotinylated MIP-1 alpha molecule to nor mal and CML CD34(+) cells. Flow cytometric analysis of the MIP-1 alpha rece ptor subtype CCR-5 revealed comparable CCR-5 expression levels on normal an d CML CD34(+) cells. Furthermore, culture of CD34(+) cells for 10 h in the presence of TNF-alpha resulted in an increased MIP-1 alpha receptor express ion on both normal and CML CD34(+) cells. Our data suggest that the unrespo nsiveness of CML CFC to the growth inhibitory effect of MIP-1 alpha is not caused by a lack of MIP-1 alpha receptor or total uncoupling of the MIP-1 a lpha responsiveness but may be due to an intracellular signalling defect do wnstream of the receptors.