The Role of JAK2 in Myeloproliferative Neoplasms

Lally, James (2017) The Role of JAK2 in Myeloproliferative Neoplasms. PhD thesis, University of Lincoln.

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The Role of JAK2 in Myeloproliferative Neoplasms
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Abstract

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.

Divisions:College of Science > School of Life Sciences
ID Code:37652
Deposited On:04 Oct 2019 14:51

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