There is accumulating evidence that myeloproliferative neoplasms (MPNs) are characterized by accelerated replicative and cellular aging: telomeres are significantly shortened and correlated with disease progression and various compounds that target telomerase function revealed promising effects in preclinical and clinical studies. However, the state of cellular aging in MPN subsets has not yet been analyzed systematically and little is known on how the MPN driver mutations impact on this process. This subproject is investigating
- different pheno- and genotypes of cellular aging-associated changes during disease progression in different cellular subpopulations of MPN patients by analyzing telomere length, various senescence markers, MPN mutations, and age-associated DNA methylation changes in different cellular subsets, in colony forming units, and in the stromal compartment,
- how MPN driver mutations affect clonal development, genetic instability and cellular aging utilizing utilize patient-specific induced pluripotent stem cell (iPSC) models, and
- if clonal and non-clonal cellular MPN subpopulations with accelerated aging are more susceptible to specific senolytic drugs and telomerase inhibitors by testing various compounds, including Imetelstat, Dasatinib, Quercetin, and FOXO4-DRI peptide on primary MPN samples and iPSC-derived hematopoietic cells.
This knowledge shall contribute to a better understanding of the pathophysiology of clonal (as well as non-clonal) disease development, provide new epigenetic biomarkers to track the disease, and facilitate new therapeutic concepts for targeting of senescent cells.