1 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms, in which a stem cell lesion induces an autonomous proliferative advantage. In addition to the JAK2V617 mutation several other mutations have been described. Recently chronic inflammation has been proposed as a trigger and driver of clonal evolution in MPNs. Herein, it is hypothesized that sustained inflammation may elicit the stem cell insult by inducing a state of chronic oxidative stress with elevated levels of reactive oxygen species (ROS) in the bone marrow, thereby creating a high-risk microenvironment for induction of mutations due to the persistent inflammation-induced oxidative damage to DNA in hematopoietic cells. Alterations in the epigenome induced by the chronic inflammatory drive may likely elicit a "epigenetic switch" promoting persistent inflammation. The perspectives of chronic inflammation as the driver of mutagenesis in MPNs are discussed, including early intervention with interferon-alpha2 and potent anti-inflammatory agents (e.g. JAK1-2 inhibitors, histone deacetylase inhibitors, DNA-hypomethylators and statins) to disrupt the self-perpetuating chronic inflammation state and accordingly eliminating a potential trigger of clonal evolution and disease progression with myelofibrotic and leukemic transformation.
Leukemia Research, 2013, Vol 37, Issue 2, p. 214-20