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Title: The role of JAK2 in myeloproliferative neoplasms
Author: Lally, James
Awarding Body: University of Lincoln
Current Institution: University of Lincoln
Date of Award: 2017
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Myeloproliferative Neoplasms (MPNs) are a group of clonally derived stem-cell disorders of haematopoietic progenitors resulting in a proliferation of differentiated myeloid cell types. They include polycythaemia vera (PV), essential thrombocythaemia (ET), and myelofibrosis (MF). JAK2 encodes a non-receptor tyrosine kinase and mutations in this gene are found in a large percentage of MPN cases. It is present in approximately 95% of PV and between 50-60% of ET and PMF cases. JAK2 plays a key role in cell proliferation and differentiation of haematopoietic stem cells to mature blood cells. Expression of key haematopoietic genes were studied along with their relationship to haematological parameters and JAK2 mutational status. Anagrelide was used to target the haematopoietic transcription factor, GATA1, in MPN model cell lines. The effect of this drug on downstream effectors of megakaryocytic differentiation was also studied to determine potential mechanisms for its antiplatelet activity in essential thrombocythaemia. Ruxolitinib, a JAK1/2 inhibitor, was used to block JAK2 and the downstream effects on STAT, SOCS and interferon-gamma target proteins were quantified. Global proteomic changes were studied, using isobaric tagging and relative quantification and LCMS/MS. This inhibitor was also used to examine the importance of JAK2 signalling in erythropoiesis and colony growth in primitive progenitor cells isolated from MPN patients. GATA1 expression was found to be dysregulated in the PBMCs of ET patients. In cell lines, expression of downstream GATA1 targets were found to be downregulated during inhibition of megakaryopoiesis using anagrelide. Functional protein analysis showed that STAT1 and associated key molecular pathways involved in interferon signalling were the target of JAK2 inhibition by ruxolitinib. The results in this study suggest a potential role for GATA1 as a disease biomarker, independent of JAK2 mutational status. The activity of the anti-platelet drug, anagrelide, may in part be due to targeting of GATA1 downstream targets. STAT1 is likely to play a key role in MPN pathogenesis and response to JAK inhibitor therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available