ABL PROTEIN-KINASE ABROGATES THE RESPONSE OF MULTIPOTENT HEMATOPOIETIC-CELLS TO THE GROWTH INHIBITOR MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA

The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal haemopoietic progenitor cells, are resistant to the growth inhibitory effects of the chemokine macrophage inflammatory protein-1 alpha (MIP -1 alpha). CML is also relatively resistant to chemotherapy and the di sease is difficult to cure using conventional therapeutic routes, CML is associated with increased abl oncogene protein tyrosine kinase (PTK ) activity. Here, we have tested the hypothesis that these aberrant re sponses to MIP-1 alpha and the relative resistance to chemotherapy are directly related to this increased abl PTK activity in primitive haem opoietic cells. to do this we have expressed a temperature sensitive a bl PTK in a growth factor dependent, multipotent stem cell line (FDCP- Mix) in which growth is normally suppressed by MIB-1 alpha. In FDCP-Mi x cells expressing the ts v-abl PTK and grown at the restrictive tempe rature for PTK activity the cells were relatively sensitive to cytotox ic agents such as cytosine arabinoside and 5-fluorouracil but MTP-1 al pha could induce growth inhibition and confer some degree of protectio n from these agents. At the permissive temperature for abl PTK, the ce lls were relatively resistant to cytotoxic drugs and MIP-1 alpha treat ment neither induced growth inhibition nor protected the cells from cy totoxic drug induced cell death. This lack of response to MIP-1 alpha was not due to receptor down modulation as neither the affinity nor th e number of I-125-MIP-1 alpha binding sites was altered by activating Abl PTK. However, MIP-1 alpha mediated increases in cytosolic Ca2+ lev els were abrogated by switching cells to the permissive temperature fo r Abl PTK activity. These data suggest that the relative resistance of CML progenitor cells to therapeutic drugs and the lack of response to MIP-1 alpha occurs as a direct consequence of abl PTK activity and in volves desensitisation of signal transduction events stimulated by MIP -1 alpha receptors. Thus one contributory mechanism to transformation of primitive haemopoietic cells is abrogation of response to a growth inhibitor.