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dc.contributor.authorPearson, Stella
dc.contributor.authorWilliamson, Andrew J K
dc.contributor.authorBlance, Rognvald N
dc.contributor.authorSomervaille, Tim C P
dc.contributor.authorTaylor, Sam
dc.contributor.authorAzadbakht, Narges
dc.contributor.authorWhetton, Anthony D
dc.contributor.authorPierce, Andrew
dc.date.accessioned2017-06-29T10:39:31Z
dc.date.available2017-06-29T10:39:31Z
dc.date.issued2017-05-23
dc.identifier.citationProteomic analysis of JAK2V617F induced changes identifies potential new combinatorial therapeutic approaches. 2017 Leukemiaen
dc.identifier.issn1476-5551
dc.identifier.pmid28533538
dc.identifier.doi10.1038/leu.2017.143
dc.identifier.urihttp://hdl.handle.net/10541/620423
dc.description.abstractIn 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.
dc.language.isoenen
dc.rightsArchived with thanks to Leukemiaen
dc.titleProteomic analysis of JAK2V617F induced changes identifies potential new combinatorial therapeutic approaches.en
dc.typeArticleen
dc.contributor.departmentStem Cell and Leukaemia Proteomics Laboratory, Manchester Academic Health Science Centre, The University of Manchester, Wolfson Molecular Imaging Centre, Withington, Manchester, UKen
dc.identifier.journalLeukemiaen
refterms.dateFOA2018-12-17T14:56:47Z
html.description.abstractIn 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.


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