BCR–ABL alters the proliferation and differentiation response of multipotent hematopoietic cells to stem cell factor

Abstract

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.