title: The coupling of TEL/PDGFbetaR to distinct functional responses is modulated by the presence of cytokine: involvement of mitogen-activated protein kinases.
abstract: The TEL/PDGFbetaR 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 signaling events activated by TEL/PDGFbetaR to functional responses, we expressed TEL/PDGFbetaR in interleukin 3 (IL-3)-dependent BaF/3 cells using the tetracycline-regulated expression system. Induction of TEL/PDGFbetaR 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 mitogen-activated protein kinase (MAPK) pathways. However, inducible expression of TEL/PDGFbetaR failed to generate factor-independent cells, whereas constitutive expression of TEL/PDGFbetaR did, albeit at low frequency, suggesting the duration of TEL/PDGFbetaR expression is important for transformation. Surprisingly, in cells induced to express TEL/PDGFbetaR, IL-3-dependent growth was dramatically reduced as a result of increased apoptosis of cells receiving combined IL-3 and TEL/PDGFbetaR signals. We demonstrate that TEL/PDGFbetaR expression augmented IL-3-induced activation of PKB, STAT5, ERK1/2, p38, and JNK1/2. Inhibition of neither phosphoinositide-3 kinases nor p38 MAPKs reduced the inhibition of IL-3-driven proliferation observed when TEL/PDGFbetaR was expressed. However, inhibition of MEKs or JNKs partially reversed the combined inhibitory effects of TEL/PDGFbetaR and IL-3 on proliferation and survival. These results suggest that the combination of TEL/PDGFbetaR 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.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Wheadon
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Welham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
chemical_list: D016207:Cytokines; D004121:Dimethyl Sulfoxide; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D020928:Mitogen-Activated Protein Kinases; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015534:Trans-Activators; C120888:TEL-PDGFRbeta fusion protein, human