title: Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development?
abstract: 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.
authors.affiliation: Department of Hematology, Roskilde Hospital, University of Copenhagen, Køgevej 7-13, Roskilde, Denmark. hans.hasselbalch@dadlnet.dk
authors.forename: Hans Carl
authors.initials: HC
authors.lastname: Hasselbalch
mesh_terms: D000818:Animals; D019046:Bone Marrow Neoplasms / Q000209:etiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002908:Chronic Disease; D018450:Disease Progression; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000235:genetics / Q000821:virology; D053614:Janus Kinase 2 / Q000235:genetics; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics; D011087:Polycythemia Vera / Q000209:etiology* / Q000235:genetics; D055728:Primary Myelofibrosis / Q000209:etiology* / Q000235:genetics; D015398:Signal Transduction; D055153:Stem Cell Niche; D013920:Thrombocythemia, Essential / Q000209:etiology* / Q000235:genetics
chemical_list: D053614:Janus Kinase 2