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

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.