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

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Abstract
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-κB. 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-κB 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 IκBα. Because both conditions inactivate NF-κB 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-κB, had a similar effect. We conclude that NF-κB 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.