BCR-ABL AND CONSTITUTIVELY ACTIVE ERYTHROPOIETIN RECEPTOR (CEPOR) ACTIVATE DISTINCT MECHANISMS FOR GROWTH FACTOR-INDEPENDENCE AND INHIBITION OF APOPTOSIS IN BA F3 CELL-LINE/

The interleukin-3 dependent murine Ba/F3 cell line has been widely use d as an experimental model of cell transformation by BCR-ABL oncogenes as assessed by induction of growth-factor-independence and inhibition of apoptosis in vitro. The signaling pathways used by BCR-ABL oncogen es to exert these effects are unknown, To gain insights into this phen omenon, we have introduced the p190- and p210-encoding BCR-ABL oncogen es as well as the constitutively activated oncogenic murine erythropoi etin receptor (cEpoR) into Ba/F3 and compared the behavior of individu al clones in response to apoptotic stimuli, Both p210 and p190 BCR-ABL vectors induced IL-3-independent growth and the same result was obtai ned with the cEpo-R vector, Individual clones of Ba/F3 cells expressin g BCR-ABL exhibited significant resistance to apoptosis induced by eit her etoposide, serum deprivation or growth-factor withdrawal. In contr ast, Ba/F3 cells expressing the constitutively active cEpoR behaved li ke parental Ba/F3 cells undergoing apoptosis when similarly treated wi th etoposide or upon serum deprivation, Bc12 and Bas levels were simil ar in all BCR-ABL and cEpoR-transfected clones, However, in band-shift assays, nuclear extracts from growth-factor-independent Ba/F3 clones expressing cEpoR had no detectable STAT activity as opposed to the con stitutive STAT activation detected in all Ba/F3 clones expressing p210 or p190 BCR-ABL. Our results indicate that although both constitutive ly activated cEpoR and BCR-ABL oncogenes induce growth-factor independ ence in Ba/F3 cells, only BCR-ABL is able to protect cells from etopos ide and serum-deprivation-induced apoptosis and induce a strong consti tutive activation of STAT factors, suggesting a role for these molecul es in the anti-apoptotic activity of BCR-ABL.