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Torkil Steenbecks Legat","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009903","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006197","name":"Fonden til L\u00e6gevidenskabens Fremme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006197","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010347","name":"Fabrikant Einar Willumsens Mindelegat","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006442","name":"Det Sundhedsvidenskabelige Fakultet, K\u00f8benhavns Universitet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006442","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007438","name":"Familien Hede Nielsens Fond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007438","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Chronic inflammation is considered a major driving force for clonal expansion and evolution in the Philadelphia-negative myeloproliferative neoplasms, which include essential thrombocythemia, polycythemia vera and primary myelofibrosis (MPNs). One of the key mutation drivers is the<jats:italic>JAK2V617F<\/jats:italic>mutation, which has been shown to induce the generation of reactive oxygen species (ROS). Using whole blood gene expression profiling, deregulation of several oxidative stress and anti-oxidative defense genes has been identified in MPNs, including significant downregulation of<jats:italic>TP53<\/jats:italic>, the<jats:italic>NFE2L2<\/jats:italic>or<jats:italic>NRF2<\/jats:italic>genes. These genes have a major role for maintaining genomic stability, regulation of the oxidative stress response and in modulating migration or retention of hematopoietic stem cells. Therefore, their deregulation might give rise to increasing genomic instability, increased chronic inflammation and disease progression with egress of hematopoietic stem cells from the bone marrow to seed in the spleen, liver and elsewhere. Interferon-alpha2 (rIFN\u03b1) is increasingly being recognized as the drug of choice for the treatment of patients with MPNs. Herein, we report the first gene expression profiling study on the impact of rIFN\u03b1 upon oxidative stress and antioxidative defense genes in patients with MPNs (n = 33), showing that rIFN\u03b1 downregulates several upregulated oxidative stress genes and upregulates downregulated antioxidative defense genes. Treatment with rIFN\u03b1 induced upregulation of 19 genes in ET and 29 genes in PV including<jats:italic>CXCR4<\/jats:italic>and<jats:italic>TP53<\/jats:italic>. In conclusion, this rIFN\u03b1- mediated dampening of genotoxic damage to hematopoietic cells may ultimately diminish the risk of additional mutations and accordingly clonal evolution and disease progression towards myelofibrotic and leukemic transformation.<\/jats:p>","DOI":"10.1371\/journal.pone.0270669","type":"journal-article","created":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T17:33:30Z","timestamp":1656610410000},"page":"e0270669","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms favorably impacts deregulation of oxidative stress genes and antioxidative defense mechanisms"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0097-7826","authenticated-orcid":true,"given":"Vibe","family":"Skov","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mads","family":"Thomassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lasse","family":"Kj\u00e6r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Ellervik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten Kranker","family":"Larsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9829-3099","authenticated-orcid":true,"given":"Trine Alma","family":"Knudsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torben A.","family":"Kruse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans C.","family":"Hasselbalch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"issue":"23","key":"pone.0270669.ref001","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1056\/NEJMra063728","article-title":"Mechanisms of disease: the myeloproliferative disorders","volume":"355","author":"PJ Campbell","year":"2006","journal-title":"N Engl J Med"},{"issue":"22","key":"pone.0270669.ref002","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1056\/NEJMra1406186","article-title":"Myeloproliferative Neoplasms.","volume":"376","author":"JL Spivak","year":"2017","journal-title":"N Engl J Med"},{"issue":"11","key":"pone.0270669.ref003","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.3324\/haematol.2011.055392","article-title":"The JAK2 46\/1 haplotype: a marker of inappropriate myelomonocytic response to cytokine stimulation, leading to increased risk of inflammation, myeloid neoplasm, and impaired defense against infection?","volume":"96","author":"S Hermouet","year":"2011","journal-title":"Haematologica"},{"issue":"2","key":"pone.0270669.ref004","doi-asserted-by":"crossref","first-page":"315","DOI":"10.3324\/haematol.2010.031070","article-title":"Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin3","volume":"96","author":"T Barbui","year":"2011","journal-title":"Haematologica"},{"issue":"14","key":"pone.0270669.ref005","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1182\/blood-2011-11-394775","article-title":"Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?","volume":"119","author":"HC Hasselbalch","year":"2012","journal-title":"Blood"},{"issue":"2","key":"pone.0270669.ref006","first-page":"214","article-title":"Chronic Inflammation as a Promoter of Mutagenesis in Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis","volume":"37","author":"HC Hasselbalch","year":"2013","journal-title":"A Human Inflammation Model for Cancer Development? 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