G. Wark et al., ABL PROTEIN-KINASE ABROGATES THE RESPONSE OF MULTIPOTENT HEMATOPOIETIC-CELLS TO THE GROWTH INHIBITOR MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA, Oncogene, 16(10), 1998, pp. 1319-1324
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.