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

Dobbin, Edwina, Graham, Ciaren, Corrigan, Pamela M. , Thomas, Keith G., Freeburn, Robin W. and Wheadon, Helen (2009) Tel/PDGFRbeta induces stem cell differentiation via the Ras/ERK and STAT5 signaling pathways. Experimental Hematology, 37 (9). pp. 111-121. ISSN 0301-472x

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OBJECTIVE: Fusion genes involving the platelet-derived growth factor receptor-beta (PDGFRbeta) are found in a subgroup of myeloproliferative neoplasms, with one such fusion, Tel/PDGFRbeta found in a subset of chronic myelomonocytic leukemia patients. Tel/PDGFRbeta 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/PDGFRbeta to identify the key signaling pathways, which drive Tel/PDGFRbeta-induced differentiation of embryonic stem (ES) cells.
MATERIALS AND METHODS: The leukemic oncogene Tel/PDGFRbeta and Tel/PDGFRbeta-F2 were inducibly expressed in ES cells and their effects on self-renewal, signal transduction, and gene expression patterns analyzed.

RESULTS: Tel/PDGFRbeta 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/PDGFRbeta-induced differentiation and restore ES-cell self-renewal. Inhibiting the tyrosine kinase activity of the oncogene using Gleevec or PDGFRbeta inhibitor III also substantially prevented Tel/PDGFRbeta-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/PDGFRbeta and the MEK/ERK pathway completely preventing Tel/PDGFRbeta-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/PDGFRbeta, may result in more efficacious therapies for suppressing leukemic progression in the clinical setting.

Keywords:Embryonic Stem Cells, Signal Transduction, Tel/PDGFRbeta, STAT5, MEK/ERK
Subjects:C Biological Sciences > C130 Cell Biology
C Biological Sciences > C741 Medical Biochemistry
Divisions:College of Science > School of Life Sciences
ID Code:7323
Deposited On:21 Jan 2013 13:06

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