Activation of p65 NF-κB protein by p210BCR – ABL in a myeloid cell line (P210BCR – ABL activates p65 NF-κB)

Abstract

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 eect of p210 BCR ± ABL expression on NF-kB activity in DA1 cells (an IL-3-dependent murine myeloid progenitor cell line). A speci®c stimulation of NF-kB 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-kB may be an eector for p210 BCR ± ABL and probably contributes to its induced transformation process.

Transcription factor NF-κB is constitutively activated in acute lymphoblastic leukemia cells

“…22 The bcr-abl product of the highrisk translocation (9;22)(q34;q11) in ALL has been shown to activate NF-B through an as yet unknown target in the NF-B/I B pathway. 23,24 It is present in 5% of childhood ALL, 20% of relapsed childhood ALL and 30% of adult ALL, and thus can account for NF-B activation in some, but not all ALLs.…”

Expression of Nuclear Factor-κB, Tumor Necrosis Factor Receptor Type 1, and c-Myc in Human Astrocytomas

“…NFkB is implicated in the transformation and tumorigenicity of various cancers. 6,[13][14][15] NF-kB can stimulate the transcription of genes that may be essential for malignant transformation. An important consequence of the activation of NF-kB might be increased genomic instability, which appears to accelerate neoplastic progression.…”

Fusion tyrosine kinase mediated signalling pathways in the transformation of haematopoietic cells

“…109 Inhibition of NF-kB activity in Tel-PDGFbR and Tel-Jak2-transformed cells results in the induction of apoptotic cell death, 110,111 indicating a prosurvival role for NF-kB and consistent with the NF-kB activation observed in Bcr-Abl-transformed cells. 111,112 Antisense oligos against the predominant p65 subunit (RelA) prevented IL3 independence in these cells, suggesting a role for NF-kB in the panoply of signals whereby Bcr-Abl mediates cell growth and survival. 112 Conversely, NF-kB is apparently not active in NPM-ALK-expressing patient-derived cell lines, even though the TNFR superfamily member CD30, usually associated with NF-kB activation, is expressed on the surface of these cells.…”