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    Proteomic analysis of JAK2V617F induced changes identifies potential new combinatorial therapeutic approaches.

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    Authors
    Pearson, Stella
    Williamson, Andrew J K
    Blance, Rognvald N
    Somervaille, Tim C P
    Taylor, Sam
    Azadbakht, Narges
    Whetton, Anthony D
    Pierce, Andrew
    Affiliation
    Stem Cell and Leukaemia Proteomics Laboratory, Manchester Academic Health Science Centre, The University of Manchester, Wolfson Molecular Imaging Centre, Withington, Manchester, UK
    Issue Date
    2017-05-23
    
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    Abstract
    In excess of 90% of patients with polycythemia vera express a mutated form of JAK2, JAK2V617F. Such aberrant proteins offer great potential for the treatment of these diseases however inhibitors to JAK2 have had limited success in the clinic in terms of curing the disease. To understand the effects of this oncogene in hematopoietic cells with the aim of improving treatment strategies we undertook a systematic evaluation of the effects of JAK2V617F expression using proteomics. The effects of JAK2V617F on over 5000 proteins and 2000 nuclear phosphopeptides sites were relatively quantified using either SILAC or eight channel iTRAQ mass spectrometry. Pathway analysis of the proteins identified as changing indicated disruption to the p53 and MYC signalling pathways. These changes were confirmed using orthogonal approaches. The insight gained from this proteomic analysis led to the formation of hypothesis driven analysis on inhibitor mediated effects on primary cells from patients with a JAK2V617F mutation. Simultaneous inhibition of MYC and up-regulation of p53 led to the preferential extinction of JAK2V617F positive CD34+ cells illustrating a potential therapeutic benefit from combined targeting of p53 and MYC.Leukemia accepted article preview online, 23 May 2017. doi:10.1038/leu.2017.143.
    Citation
    Proteomic analysis of JAK2V617F induced changes identifies potential new combinatorial therapeutic approaches. 2017 Leukemia
    Journal
    Leukemia
    URI
    http://hdl.handle.net/10541/620423
    DOI
    10.1038/leu.2017.143
    PubMed ID
    28533538
    Type
    Article
    Language
    en
    ISSN
    1476-5551
    ae974a485f413a2113503eed53cd6c53
    10.1038/leu.2017.143
    Scopus Count
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