Submitted October 10, 2002
Accepted April 10, 2003
The coupling of TEL/PDGF
R to distinct functional responses is modulated by the presence of cytokine: involvement of mitogen-activated protein kinases
Helen Wheadon and Melanie J Welham*
Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom
* Corresponding author; email: prsmjw{at}bath.ac.uk.
The TEL/PDGF
R oncogenic fusion protein is the product of the t(5;12)(q33; p13) translocation recurrently found in patients with chronic myelomonocytic leukemia (CMML). To investigate the coupling of molecular signalling events activated by TEL/PDGFR to functional responses, we expressed TEL/PDGFR in interleukin-3 (IL-3)-dependent BaF/3 cells using the Tet-regulated expression system. Induction of TEL/PDGFR expression led to increased cell survival following IL-3 withdrawal and constitutive activation of protein kinase B (PKB), signal transducer and activator of transcription 5 (STAT5), extracellular-signal regulated kinases 1/2 (ERK1/2), Jun N-terminal kinases 1/2 (JNK1/2) and p38 MAPK pathways. However, inducible expression of TEL/PDGFR failed to generate factor-independent cells, whereas constitutive expression of TEL/PDGFR did, albeit at low frequency, suggesting the duration of TEL/PDGFR expression is important for transformation. Surprisingly, in cells induced to express TEL/PDGFR, IL-3-dependent growth was dramatically reduced as a result of increased apoptosis of cells receiving combined IL-3 and TEL/PDGFR signals. We demonstrate that TEL/PDGFR expression augmented IL-3-induced activation of PKB, STAT5, ERK1 and 2, p38 and JNK1 and 2. Inhibition of neither phosphoinositide-3 kinases or p38 MAPKs reduced the inhibition of IL-3-driven proliferation observed when TEL/PDGFR was expressed. However, inhibition of MEKs or JNKs partially reversed the combined inhibitory effects of TEL/PDGFR and IL-3 on proliferation and survival. These results suggest that the combination of TEL/PDGFR and IL-3-induced signals activate apoptosis through ERK and JNK MAPK-dependent pathways. Given that in vivo hematopoietic cells are in contact with a variety of cytokines, our results have important implications for cellular responses in the pathogenesis of CMML.
