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@PHDTHESIS{Holl:992265,
author = {Holl, Kristin Joana},
othercontributors = {Antonin, Wolfram and Pradel, Gabriele},
title = {{E}ffect of calreticulin and {JAK}2{V}617{F} driver
mutations on mitotic progression in myeloproliferative
neoplasms},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2024-08104, 692077 - 108/20},
pages = {1 Online-Ressource : Illustrationen},
year = {2024},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2024},
abstract = {Myeloproliferative neoplasms (MPN) are diseases of
haematopoietic stem cells caused by somatic mutations and
clonal expansion of mutated haematopoietic stem and
progenitor cells (HSPC). MPNs manifest in various clinical
pictures. The most commons are chronic myeloid leukaemia
(CML), essential thrombocythemia (ET), polycythaemia vera
and primary myelofibrosis (PMF). The present work focuses on
Philadelphia-negative MPNs caused by mutations in the Janus
Kinase 2 (JAK2) and the calreticulin (CALR).The prevailing
working model assumes that the influence of the cellular
microenvironment and the acquisition of additional mutations
lead to heterogeneous diseases caused by these driver
mutations. In the present study, I demonstrate an increased
incidence of chromatin segregation defects in haematopoietic
cells with stable expression of the mutations CALRdel52 or
JAK2V617F. In addition, my studies on murine 32DMPL and
human erythroleukemic TF-1MPL cells showed a correlation
between the expression of CALRdel52 or JAK2V617F and a
defective spindle assembly checkpoint (SAC). This
contributes to defective mitosis, which can lead to
aneuploidy and tumorigenesis. Overall, this promotes
defective mitosis. Further analysis showed that when
CALRdel52 or JAK2V617F is expressed, there is a correlation
between a defective SAC and an imbalance in the recruitment
of SAC factors to mitotic kinetochores. I observed a
premature degradation of Cyclin B1 during mitosis in 32DMPL
cells with CALRdel52 or JAK2V617F mutations, which is
associated with a weakening of the SAC. My analysis results
on the duration of mitosis in non-haematopoietic cells
support the hypothesis and shows the importance of a
defective SAC for non-error-free mitosis. In summary, my
research results showed that CALRdel52 or JAK2V617F MPN
driver mutations alter mitotic regulation potentially
impacting karyotype stability, which could be an important
factor for the pathogenesis of MPN.},
cin = {513000-4 ; 925510 / 164020 / 160000},
ddc = {570},
cid = {$I:(DE-82)513000-4_20140620$ / $I:(DE-82)164020_20200124$ /
$I:(DE-82)160000_20140620$},
pnm = {ERS StUpPD-108/20 - Mitotic progression in hematopoietic
malignancies (StUpPD-108/20) / ERS Start-Up (EXS) - Start-Up
for Juniorprofessor and Postdocs (EXS-SU) / Excellence
Strategy},
pid = {G:(ERS)StUpPD-108/20 / G:(DE-82)EXS-SU / G:(DE-82)EXS},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2024-08104},
url = {https://publications.rwth-aachen.de/record/992265},
}
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