Evidence for a role of NF-κB in the survival of hematopoietic cells mediated by interleukin 3 and the oncogenic TEL/platelet-derived growth factor receptor β fusion protein

Interleukin 3 (IL-3) and other hematopoietic cytokines transduce signals that stimulate DNA synthesis and cell survival, In certain chronic myelomonocytic leukemias, a TEL/platelet-derived growth factor receptor beta (PDGFR beta) fusion protein is produced as a consequence of the t(5;12) translocation. It contains the amino terminus of the transcription factor TEL fused to the transmembranous and cytoplasmic domains of the PDGFR beta. It is oncogenic as it substitutes for IL-3, thus promoting cell growth and preventing apoptotic cell death. The mechanism by which TEL/PDGFR beta generates survival signals remains undefined, Here, we report that both IL-3 and TEL/PDGFR beta initiate a signaling cascade that leads to the activation of the transcriptional factor NF-kappa B, In fact, either cytokine deprivation of IL3-dependent Ba/F3 cells or exposure of TEL/PDGFR beta-expressing cells to the specific inhibitor of the PDGFlR tyrosine kinase, CGP53716, caused a strong decrease in NF-kappa B activity followed by extensive cell death. Further, treatment with the proteasome inhibitor Z-IE(O-t-Bu)A-leucinal suppressed IL-3 and TEL/PDGFR beta-dependent survival. The same result,vas seen upon overexpression of an unphosphorylable form of I kappa B alpha. Because both conditions inactivate NF-kappa B by preventing its translocation into the nucleus, that process seems to be essential for cell survival in response to IL-3 and TEL/PDGFR beta, Moreover, overexpression of a dominant-negative mutant of the protooncogene c-Myc, a downstream target of NF-kappa B, had a similar effect. We conclude that NF-kappa B plays an important role in maintaining cell survival in response to IL-3 and TEL/PDGFR beta and that c-Myc may be a downstream effector mediating this effect.