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%0 Thesis %A Tharmapalan, Vithurithra %T Cellular aging in myeloproliferative neoplasms %I RWTH Aachen University %V Dissertation %C Aachen %M RWTH-2025-01949 %P 1 Online-Ressource : Illustrationen %D 2025 %Z Veröffentlicht auf dem Publikationsserver der RWTH Aachen University %Z Dissertation, RWTH Aachen University, 2025 %X 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. %F PUB:(DE-HGF)11 %9 Dissertation / PhD Thesis %R 10.18154/RWTH-2025-01949 %U https://publications.rwth-aachen.de/record/1005703