Methylation age as a correlate for allele burden, disease status, and clinical response in myeloproliferative neoplasm patients treated with vorinostat

The myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal neoplastic disorders. Driver mutations in JAK2, CALR, and MPL genes have been identified in the majority of cases. Alongside these, an increasing number of genes are repeatedly identified as mutated in MPN. These, including ASXL1, TET2, DMNT3A, and EZH2, have key roles in epigenetic regulation. Dysregulation of epigenetic processes is therefore a key feature of MPN. Vorinostat is a pan histone deacetylase inhibitor (HDACi) that has been investigated in MPN. DNA methylation (DNAm) is a well-defined epigenetic mechanism of transcription modification. It is known to be affected by ageing, lifestyle, and disease. Epigenetic ageing signatures have been previously described allowing calculation of a methylation age (MA). In this study we examined the effect of vorinostat on MA in MPN cell lines and in patients with polycythaemia vera (PV) and essential thrombocythaemia (ET) treated with vorinostat as part of a clinical trial. An older MA was observed in patients with a higher JAK2 V617F allele burden and those with a longer duration of disease. PV patients had a MA older than that predicted whilst MA was younger than predicted in ET. Treatment with vorinostat resulted in a younger MA in PV patients and older MA in ET patients, in both cases a trend towards the normal chronological age. When MA change was compared against response, nonresponse was associated with a younger than predicted MA in ET patients and a higher than predicted MA in PV patients. The link between MA and JAK2 mutant allele burden implies that allele burden has a role not only in clinical phenotype and disease evolution in MPN patients, but also in the overall methylation landscape of the mutated cells.