BCR-ABL alters the proliferation and differentiation response of multipotent hematopoietic cells to stem cell factor.
Chronic myeloid leukaemia (CML), a hematopoietic stem cell disorder is characterized by the expression of BCR-ABL. To investigate the effects of BCR-ABL on multipotent hematopoietic cells, a temperature sensitive BCR-ABL tyrosine kinase was expressed in the cell line, FDCP-Mix. BCR-ABL mediated an increase in c-kit expression that correlated with an enhanced mitogenic response to SCF. This was not observed in the absence of Bcr-Abl kinase activity or presence of the BCR-ABL inhibitor STI571, which also inhibits c-kit. When cultured in a combination of SCF plus G-CSF the FDCP-Mix cells undergo neutrophilic differentiation over a 7-10 day period. When BCR-ABL was active there was a marked inhibition of cell maturation compared to control cells in which BCR-ABL was either inactive or not present. However, BCR-ABL did not block differentiation as the cells eventually undergo terminal maturation. These data argue that BCR-ABL is directly responsible for the enhanced response to SCF reported in CML progenitor cells. Furthermore, although the primary effect of STI571 is via direct inhibition of BCR-ABL, STI571 additionally reduces the enhanced response to SCF. Thus there are two sites of STI571 action of potential importance in Bcr-Abl expressing cells.
Pierce
Andrew
A
Department of Biomolecular Sciences, Leukaemia Research Fund Cellular Development Unit, UMIST, Sackville Street, Manchester M60 1QD, UK.
Spooncer
Elaine
E
Ainsworth
Shaun
S
Whetton
Anthony D
AD
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D009504:Neutrophils / Q000166:cytology; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D019089:Stem Cell Factor / Q000494:pharmacology*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl