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


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.


CONCLUSIONS
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.
Dobbin
Edwina
E
Stem Cell and Epigenetics Research Group, Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland.
Graham
Ciaren
C
Corrigan
Pamela M
PM
Thomas
Keith G
KG
Freeburn
Robin W
RW
Wheadon
Helen
H
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein
D048049:Extracellular Signal-Regulated MAP Kinases; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D050783:Proto-Oncogene Proteins c-ets; D020797:Receptor, Platelet-Derived Growth Factor beta; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D018631:ras Proteins; D000097764:ETS Translocation Variant 6 Protein; C494087:Stat3 protein, mouse