BCR-ABL KINASE PROMOTES CELL-CYCLE ENTRY OF PRIMARY MYELOID CML CELLSIN THE ABSENCE OF GROWTH-FACTORS

Cell cycle control of both immature and differentiated primary myeloid normal and chronic-phase chronic myeloid leukaemia (CML) cells to gro wth factor deprivation was studied. CD34(+) cells were cultured in liq uid culture. After removal of growth factors for 48 h normal cells wer e very efficiently arrested with the fraction of cells in S phase redu ced by 70.8 +/- 6.5% in CD34(+) and 50.5 +/- 4.2% in CD34(-) cells. In contrast, a significantly higher proportion of leukaemic cells remain ed in S phase. The fraction of S-phase cells was reduced by only 29.3 +/- 5.7% in CD34(+) CML cells and 21.2 +/- 3.8% in CD34(-) cells. This abnormal negative cell cycle control in leukaemic cells was specific for growth factor deprivation. Reaction to IFN-alpha and TNF-alpha tre atment was identical both in normal and CML cells. Equal quantities of the cytokines TNF-alpha, IL-1 alpha, IL-1RA and IL-6 were produced by CML and normal cells. However, production of GM-CSE with a median of 11 +/- 5 pg/ml, was found only in the supernatants of CML cells. But a ntibodies to GM-CSF did not restore growth factor dependence of the le ukaemic cells. The defect was completely corrected by the abl-specific tyrosine kinase inhibitor CGP 57148 without effecting cell cycle cont rol of normal cells. Our results demonstrate a directly Bcr-Abl-depend ent defective response of both immature and differentiated primary mye loid CML cells to growth factor deprivation.