Bcr-Abl kinase promotes cell cycle entry of primary myeloid CML cells in 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 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.
Jonuleit
T
T
Department of Haematology, Robert Bosch Hospital, Stuttgart, Germany.
Peschel
C
C
Schwab
R
R
van der Kuip
H
H
Buchdunger
E
E
Fischer
T
T
Huber
C
C
Aulitzky
W E
WE
D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000494:pharmacology*; D006133:Growth Substances / Q000378:metabolism; D006412:Hematopoietic Stem Cells; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology
D001549:Benzamides; D004791:Enzyme Inhibitors; D006133:Growth Substances; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl