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

Edwina Dobbin, Ciaren Graham, Pamela M. Corrigan, Keith G. Thomas, Robin W. Freeburn, Helen Wheadon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
JournalExperimental Hematology
Volume37
Issue number1
DOIs
Publication statusPublished - 01 Jan 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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