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To explore the mechanism of ruxolitinib's limited effect, we examined the JAK1\/2 mediated induction of proliferation related ERK1\/2 and AKT signaling by proinflammatory interleukin\u20106 (IL\u20106) in MPN granulocytes and\n                      <jats:italic>JAK2<\/jats:italic>\n                      V617F mutated human erythroleukemia (HEL) cells. We found that JAK1\/2 or JAK2 inhibition prevented the IL\u20106 activation of STAT3 and AKT pathways in polycythemia vera and HEL cells. Further, we showed that these inhibitors also blocked the IL\u20106 activation of the AKT pathway in primary myelofibrosis (PMF). Only JAK1\/2 inhibitor ruxolitinib largely activated ERK1\/2 signaling in essential thrombocythemia and PMF (up to 4.6 fold), with a more prominent activation in\n                      <jats:italic>JAK2<\/jats:italic>\n                      V617F positive granulocytes. Regarding a cell cycle, we found that IL\u20106 reduction of HEL cells percentage in G2M phase was reversed by ruxolitinib (2.6 fold). Moreover, ruxolitinib potentiated apoptosis of PMF granulocytes (1.6 fold). Regarding DNA replication, we found that ruxolitinib prevented the IL\u20106 augmentation of MPN granulocytes frequency in the S phase of the cell cycle (up to 2.9 fold). The inflammatory stimulation induces a cross\u2010talk between the proliferation linked pathways, where JAK1\/2 inhibition is compensated by the activation of the ERK1\/2 pathway during IL\u20106 stimulation of DNA replication.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cbin.11084","type":"journal-article","created":{"date-parts":[[2018,12,20]],"date-time":"2018-12-20T13:24:17Z","timestamp":1545312257000},"page":"192-206","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["IL\u20106 stimulation of DNA replication is JAK1\/2 mediated in cross\u2010talk with hyperactivated ERK1\/2 signaling"],"prefix":"10.1002","volume":"43","author":[{"given":"Tijana","family":"Suboti\u010dki","sequence":"first","affiliation":[{"name":"Department of Molecular Oncology Institute for Medical Research, University of Belgrade Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivera","family":"Mitrovi\u0107 Ajti\u0107","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Institute for Medical Research, University of Belgrade Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojana B.","family":"Beleslin\u2010\u010coki\u0107","sequence":"additional","affiliation":[{"name":"Clinic for Endocrinology, Diabetes and Metabolic Diseases Genetic Laboratory, Clinical Center of Serbia Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun\u010dica","family":"Bjelica","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Institute for Medical Research, University of Belgrade Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragoslava","family":"Djiki\u0107","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Institute for Medical Research, University of Belgrade Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milo\u0161","family":"Dikli\u0107","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Institute for Medical Research, University of Belgrade Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danijela","family":"Lekovi\u0107","sequence":"additional","affiliation":[{"name":"Clinic of Hematology Clinical Center of Serbia Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjana","family":"Goti\u0107","sequence":"additional","affiliation":[{"name":"Clinic of Hematology Clinical Center of Serbia Belgrade Serbia"},{"name":"School of Medicine University of Belgrade Belgrade Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan F.","family":"Santibanez","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Institute for Medical 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