Cellular aging is accelerated in the malignant clone of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are caused by somatic driver mutations, such as JAK2V617F, which might also affect cellular aging and senescence. Here, we analyzed the heterogeneity of aging in MPN patients and if this can be used to specifically target malignant cells. The mean epigenetic age was significantly accelerated in 129 MPN patients across all disease-entities, whereas premature telomere attrition was particularly observed in primary myelofibrosis. Overall, accelerated cellular aging correlated with JAK2V617F allele frequency and was more pronounced in colony forming cells with JAK2V617F as compared to JAK2 wild- type colonies. JAK2V617F mutation did not evoke clear acceleration of aging in syngeneic iPSC models upon short-term hematopoietic differentiation. On the other hand, a murine Jak2V617F model revealed epigenetic age-acceleration that therefore appears as sequel of disease progression. To investigate if the malignant clone might be targeted, we tested eight senolytic compounds, of which JQ1 and piperlongumine showed a reduction in allele burden and an increase in telomere length. Notably, treatment with the telomerase inhibitor BIBR-1532 reduced mutated colonies, particularly in patients with preexisting short telomeres. Our results indicate that cellular aging is accelerated in malignant MPN clones and this can provide a target for treatment with senolytic drugs or telomerase inhibitors.