Tel/PDGFRβ induces stem cell differentiation via the Ras/ERK and STAT5 signaling pathways

Dobbin, E., Graham, C., Corrigan, P., Thomas, K., Freeburn, R. and Wheadon, H. (2009) Tel/PDGFRβ induces stem cell differentiation via the Ras/ERK and STAT5 signaling pathways. Experimental Hematology, 37(1), pp. 111-121. (doi:10.1016/j.exphem.2008.09.012)

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Abstract

Objective: Fusion genes involving the platelet-derived growth factor receptor-β (PDGFRβ) are found in a subgroup of myeloproliferative neoplasms, with one such fusion, Tel/PDGFRβ found in a subset of chronic myelomonocytic leukemia patients. Tel/PDGFRβ results in constitutive activation of several signaling pathways and induces a myeloproliferative disease in mice, with signals via tyrosines 579/581 identified as being important for this phenotype. In this study, we have used a tetracycline-regulated system to express wild-type and the mutated F2 Tel/PDGFRβ to identify the key signaling pathways, which drive Tel/PDGFRβ-induced differentiation of embryonic stem (ES) cells. Materials and Methods: The leukemic oncogene Tel/PDGFRβ and Tel/PDGFRβ-F2 were inducibly expressed in ES cells and their effects on self-renewal, signal transduction, and gene expression patterns analyzed. Results: Tel/PDGFRβ activated several major signal transduction pathways (signal transducers and activators of transcription [STAT] 3, STAT5, mitogen-activated protein kinases, phosphatidylinositol-3 kinase) in ES cells, but only specific inhibition of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) or STAT5 pathways was able to significantly prevent Tel/PDGFRβ-induced differentiation and restore ES-cell self-renewal. Inhibiting the tyrosine kinase activity of the oncogene using Gleevec or PDGFRβ inhibitor III also substantially prevented Tel/PDGFRβ-induced differentiation and its ability to upregulate key genes involved in myelopoiesis. Tyrosines 579/581 played a critical role in mediating signals via the Ras/ERK and STAT5 pathways, with dual targeting of the tyrosine kinase activity of Tel/PDGFRβ and the MEK/ERK pathway completely preventing Tel/PDGFRβ-induced differentiation. Conclusion: These findings suggest that targeted disruption of key signaling pathways in combination with the tyrosine kinase activity of leukemic oncogenes, such as Tel/PDGFRβ, may result in more efficacious therapies for suppressing leukemic progression in the clinical setting.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dobbin, Dr Edwina and Wheadon, Dr Helen
Authors: Dobbin, E., Graham, C., Corrigan, P., Thomas, K., Freeburn, R., and Wheadon, H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Experimental Hematology
ISSN:0301-472X
Published Online:19 December 2008

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