The Effects of Aging on Profiling Epigenetic Changes in Myeloproliferative Neoplasms

Epigenetic changes in myeloproliferative neoplasms (MPNs) have been identified and characterized regarding the effects of aging and therapeutic pathways, according to a recent review. These changes help researchers understand how epigenetic changes affect patients with MPNs and the progression of this rare disease.

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In the current study, researchers aimed to review the current knowledge and understanding of epigenetics in patients with MPNs to evaluate and improve management of the disease.

“Reversible epigenetic changes and epigenetic regulation are part of the pathogenesis of MPNs both in the disease development and in progression,” the researchers wrote. “Epigenetic changes in MPN have been investigated with a variety of results.”

The full review is published in Frontiers in Oncology.

Epigenetic changes are reversible modifications to chromatin structure, histone modifications, and DNA methylation, and they are responsible for how genes are either expressed or silenced. Alterations in these structures may result in downstream gene expression changes that may influence the initiation, maintenance, or progression of a malignant cell.

In MPNs, the 3 most common pathogenetic mutations identified were epigenetic regulators: TET2, ASXL1, and DNMT3A, which were present at frequencies above 5% in an unselected MPN patient population. Additionally, EZH2 occurred in approximately 2% of patients with MPN overall and appear particularly important in determining disease progression. The mutations affect the regulation of DNA histone methylation in the hemopoietic stem cell (HSC) compartment. Furthermore, ASXL1, EZH2, IDH1/2, and TET2 were implicated in the progression to fibrotic leukemic transformations and reduced survival.

Additionally, the researchers identified nuclear factor erythroid 2 (NFE2) as a transcription factor that was overexpressed in most patients with MPN. One study found insertions and deletions of NFE2 were described in approximately 2% of patients with MPN. Furthermore, NFE2 mutations were found to be a predictive variable in determining the risk of fibrotic transformation among a large cohort of patients with MPNs with chronic stage disease.

Most studies on DNA methylation have been conducted on a gene-by-gene basis, as well as in comprehensive methylation profiling studies. In a global DNA methylation study of patients with polycythemia vera, essential thrombocythemia, myelofibrosis, including some patients who had transformed to acute myeloid leukemia (AML), MPN samples showed an aberrant methylation pattern compared with control samples. However, samples were similar across the 3 disease types. Furthermore, patients with transformed AML had an increased number of differently methylated regions compared with chronic cases. Therefore, the researchers believe that altered DNA mutations may be associated with the pathogenesis of leukemic transformations in MPNs.

DNA methylation was found to be affected by aging, lifestyle, diet, and disease, so methylation age may be a more accurate describer of disease than chronological age. Studies have found an older methylation age in patients with a higher JAK2V617F allelic burden and in those with a longer disease duration. Patients with polycythemia vera had an older methylation age than predicted, but methylation age was younger than predicted in patients with essential thrombocythemia, which may be attributed to the mutant allele burden.

Additionally, treatment with vorinostat (Zolinza) resulted in younger methylation age in patients with polycythemia vera and an older methylation age in patients with essential thrombocythemia, contributing to an overall trend to normal chronological age. Furthermore, nonresponse to treatment was associated with a younger than predicted methylation age in patients with essential thrombocythemia and an older predicted age in patients with polycythemia vera.

Overall, the researchers believe that these studies show the effect of aging and treatment on the epigenetic changes in MPNs.

“However, there is room for much greater investigation and understanding of epigenetic changes and events involved in progression,” wrote the researchers. “Investigation of the epigenome shows that there are a variety of therapeutic pathways available and that can be explored further leading to targeted therapy.”

Reference

Greenfield G, McMullin MF. Epigenetics in myeloproliferative neoplasms. Front Oncol. 2023;13:1206965. doi:10.3389/fonc.2023.1206965