Bcr-Abl kinase promotes cell cycle entry of primary myeloid CML cells in the absence of growth factors

Br J Haematol. 1998 Feb;100(2):295-303. doi: 10.1046/j.1365-2141.1998.00564.x.


Cell cycle control of both immature and differentiated primary myeloid normal and chronic-phase chronic myeloid leukaemia (CML) cells to growth factor deprivation was studied. CD34+ cells were cultured in liquid culture. After removal of growth factors for 48 h normal cells were very efficiently arrested with the fraction of cells in S phase reduced by 70.8 +/- 6.5% in CD34+ and 50.5 +/- 4.2% in CD34- cells. In contrast, a significantly higher proportion of leukaemic cells remained 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 treatment was identical both in normal and CML cells. Equal quantities of the cytokines TNF-alpha, IL-1alpha, IL-1RA and IL-6 were produced by CML and normal cells. However, production of GM-CSF, with a median of 11 +/- 5 pg/ml, was found only in the supernatants of CML cells. But antibodies to GM-CSF did not restore growth factor dependence of the leukaemic cells. The defect was completely corrected by the abl-specific tyrosine kinase inhibitor CGP 57148 without effecting cell cycle control of normal cells. Our results demonstrate a directly Bcr-Abl-dependent defective response of both immature and differentiated primary myeloid CML cells to growth factor deprivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides
  • Cell Cycle / drug effects*
  • Cell Division
  • Enzyme Inhibitors / pharmacology
  • Fusion Proteins, bcr-abl / pharmacology*
  • Growth Substances / metabolism
  • Hematopoietic Stem Cells
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Piperazines / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / pharmacology*
  • Pyrimidines / pharmacology


  • Benzamides
  • Enzyme Inhibitors
  • Growth Substances
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl