The role of HDAC9 in JAK2V617F-driven myeloproliferative neoplasms

Janus kinase 2 (JAK2) encodes a protein tyrosine kinase that is critical for
haematopoiesis. JAK2 functions by modulating signal transduction between the
receptor and the JAK-STAT, ERK1/2 and AKT phosphorylation signalling
pathways. The mutation, JAK2V617F, loses the ability to inhibit autophosphorylation, the result of which is a chronically active kinase which causes
aberrant signalling. The influence of JAK2V617F has yet to be fully elucidated in
haematopoietic stem cells (HSCs). In this work I present a new model for
JAK2V617F in HSCs and have identified a gene, HDAC9, that has potential as
a possible target for treatment.
In Chapter 3, I describe the experiments that explain the construction of my
model and how I probed it with the aim to characterise it with a focus on
signalling and DNA damage/DNA damage repair. An investigation into DNA
damage/repair suggests that JAK2V617F exerts both increased DNA damage
and an increased ability to repair such damage.
In Chapter 4, I provide a cross-publication dataset analysis to compare the
RNA-sequencing analysis of my data to current models and patient data to
gauge the relevance of my data. I utilise my RNA-sequencing data alongside
bioinformatic programs to explain how the data relays back to Chapter 3. I have
provided a comprehensive validation programme to validate my RNA-sequencing data through RT-PCR.
Finally in Chapter 5, I investigate the role of HDAC9 in cell signalling, cell
proliferation, and DNA damage response. The data presented within this
chapter suggests that HDAC9 is essential for JAK-STAT signalling in HSCs and
through STAT regulation, has a role in cell proliferation and DNA damage.
Altogether, these findings reveal new insight into the role of HDAC9 in
JAK2V617F expressing HSCs.