Evidence for a Role of NF-κ B 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 β (PDGFRβ ) 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 PDGFRβ . It is oncogenic as it substitutes for IL-3, thus promoting cell growth and preventing apoptotic cell death. The mechanism by which TEL/PDGFRβ generates survival signals remains undefined. Here, we report that both IL-3 and TEL/PDGFRβ initiate a signaling cascade that leads to the activation of the transcriptional factor NF-κ B. In fact, either cytokine deprivation of IL-3-dependent Ba/F3 cells or exposure of TEL/PDGFRβ -expressing cells to the specific inhibitor of the PDGFR tyrosine kinase, CGP53716, caused a strong decrease in NF-κ 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/PDGFRβ -dependent survival. The same result was seen upon overexpression of an unphosphorylable form of Iκ Bα . Because both conditions inactivate NF-κ B by preventing its translocation into the nucleus, that process seems to be essential for cell survival in response to IL-3 and TEL/PDGFRβ . Moreover, overexpression of a dominant-negative mutant of the protooncogene c-Myc, a downstream target of NF-κ B, had a similar effect. We conclude that NF-κ B plays an important role in maintaining cell survival in response to IL-3 and TEL/PDGFRβ and that c-Myc may be a downstream effector mediating this effect.