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.