Proteomic analysis reveals a novel mechanism induced by the leukemic oncogene Tel/PDGFRβ in stem cells: activation of the interferon response pathways.
Objective proteomic analysis offers opportunities for hypothesis generation on molecular events associated with pathogenesis in stem cells. Relative quantification mass spectrometry was employed to identify pathways affected by Tel/PDGFRβ, an oncogene associated with myeloproliferative neoplasia (MPN). Its effects on over 1800 proteins were quantified with high confidence. Of those up-regulated by Tel/PDGFRβ several were involved in the interferon gamma (IFNγ) response. To validate these observations we employed embryonic and myeloid stem cells models which revealed Tel/PDGFRβ-induced STAT1 up-regulation and activation was responsible for modulating the interferon response. A STAT1 target highly up-regulated was ICSBP, a transcriptional regulator of myeloid and eosinophilic differentiation. ICSBP interacts with CBP/p300 and Ets transcription factors, to promote transcription of additional genes, including the Egr family, key regulators of myelopoiesis. These interferon responses were recapitulated using IFNγ stimulation of stem cells. Thus Tel/PDGFRβ induces aberrant IFN signaling and downstream targets, which may ultimately impact the hematopoietic transcriptional factor network to bias myelomonocytic differentiation in this MPN.
Dobbin
E
E
Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, G12 0YN, UK.
Graham
C
C
Freeburn
R W
RW
Unwin
R D
RD
Griffiths
J R
JR
Pierce
A
A
Whetton
A D
AD
Wheadon
H
H
D000818:Animals; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D038042:Myelopoiesis; D020543:Proteome / Q000032:analysis*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D015854:Up-Regulation; D000097764:ETS Translocation Variant 6 Protein; D000099185:Interferon Regulatory Factor-8
D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D020543:Proteome; D050783:Proto-Oncogene Proteins c-ets; D020797:Receptor, Platelet-Derived Growth Factor beta; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D000097764:ETS Translocation Variant 6 Protein; D000099185:Interferon Regulatory Factor-8; C494080:Stat1 protein, mouse