Activation of p65 NF-kappa B protein by p210(BCR-ABL) in myeloid cell line (p210(BCR-ABL) activates p65 NF-kappa B)

The chimeric tyrosine kinase p210(BCR-ABL) is involved in the pathogenesis of chronic myelogenous leukemia. It transforms immature hematopoietic cells in vitro and abrogates IL-3-dependent growth. The mechanisms by which p210(BCR-ABL) mediates its oncogenicity are not well elucidated. Identifying transcription factors targeted by the chimeric protein may help to clarify these mechanisms. We have analysed the effect of p210(BCR-ABL) expression on NF-kappa B activity in DA1 cells (an IL-3-dependent murine myeloid progenitor cell line). A specific stimulation of NF-kappa B activity by kinase-active wild-type p210(BCR-ABL) has been evidenced by transcriptional activation assays. Electrophoretic mobility supershift assays revealed the presence of p65 protein (RelA) DNA binding activity in p210(BCR-ABL) transformed DA1 cells but not in parental DA1 cells. Activation of RelA in transformed DA1 cells may occur by protein stabilization. Experiments using oligonucleotides antisense to RelA showed that p210(BCR-ABL) transfected cells failed to survive after IL-3 removal. Moreover, inhibition of cellular growth was shown following treatment of p210(BCR-ABL) transformed DA1 cells by p65 antisense oligonucleotides. This study suggests that p65 NF-kappa B may be an effector for p210(BCR-ABL) and probably contributes to its induced transformation process.