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@PHDTHESIS{Tharmapalan:1005703,
author = {Tharmapalan, Vithurithra},
othercontributors = {Wagner, Wolfgang and Koschmieder, Steffen and Di Russo,
Jacopo},
title = {{C}ellular aging in myeloproliferative neoplasms},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2025-01949},
pages = {1 Online-Ressource : Illustrationen},
year = {2025},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2025},
abstract = {Myeloproliferative neoplasms (MPN) are a group of clonal
hematological malignancies that are caused by specific
driver mutations, such as JAK2 V617, which stimulate
abnormal cell proliferation. These MPN associated mutations
are associated with aberrant DNA methylation (DNAm)
patterns, although the underlying cause remains unclear.
This thesis aims to investigate if cellular aging is
accelerated in MPN, which might provide new therapeutic
options by senolytic molecules that selectively induce death
in senescent cells and possibly eliminate the mutant cell
population. Furthermore, we aim to better understand if the
JAK2 V617 mutation directly evokes the MPN-associated
aberrant DNAm. To address these questions, we analyzed three
cellular aging parameters, including epigenetic age,
telomere length, and cellular senescence in blood samples of
healthy donors and MPN patients. Our results indicated that
even in healthy donors, the fraction of senescent cells
tends to increase with age. Across all MPN entities, we
observed a significant acceleration of epigenetic age and
senescence associated genes, whereas telomere attrition was
particularly observed in primary myelofibrosis. Overall,
accelerated cellular aging was correlated with JAK2 V617F
allele burden and was more pronounced in JAK2 V617F mutated
colonies than their wild type counterparts. Treatment with
senolytics resulted in a significant reduction in senescent
cells and epigenetic age in healthy blood cells treated with
RG7112, JQ1, nutlin-3a and AMG232. Whereas MPN cells showed
a reduction in the JAK2 V617F allele burden and an increase
in telomere length with JQ1 and piperlongumine. Genome wide
methylation analysis of induced pluripotent stem cells
(iPSCs) and iPSC-derived hematopoietic progenitor cells with
JAK2 mutation showed no significant methylation differences
compared to wild type counterparts. However, we observed a
moderate association between shared hypomethylation patterns
in patients with the JAK2 mutation. Overall, our findings
show that cellular aging is accelerated in malignant clones,
and these cells can be targeted with senolytics. In iPSCs,
the JAK2 V617 driver mutation alone does not recapitulate
the DNAm alterations observed in MPN patients suggesting
that epigenetic changes accumulate with disease progression
rather than at early disease onset. Our results highlight
the complex interplay between cellular aging, epigenetic
changes, and the JAK2 V617F mutation in MPNs and may thereby
provide new avenues for targeting both cellular aging and
the malignant cell population. },
cin = {811002-3 ; 924120 / 160000},
ddc = {570},
cid = {$I:(DE-82)811002-3_20140620$ / $I:(DE-82)160000_20140620$},
pnm = {DFG project G:(GEPRIS)417911533 - KFO 344: Mechanismen und
molekulare Zielstrukturen der Myelofibrose in
Myeloproliferativen Neoplasien (MPN) (417911533)},
pid = {G:(GEPRIS)417911533},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2025-01949},
url = {https://publications.rwth-aachen.de/record/1005703},
}
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