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dc.creatorSubotički, Tijana
dc.creatorMitrović-Ajtić, Olivera
dc.creatorBeleslin-Čokić, Bojana
dc.creatorBjelica, Sunčica
dc.creatorĐikić, Dragoslava
dc.creatorDiklić, Miloš
dc.creatorLeković, Danijela
dc.creatorGotić, Mirjana
dc.creatorSantibanez, Juan F.
dc.creatorNoguchi, Constance T.
dc.creatorČokić, Vladan
dc.date.accessioned2021-04-20T13:03:31Z
dc.date.available2021-04-20T13:03:31Z
dc.date.issued2019
dc.identifier.issn1065-6995
dc.identifier.urihttp://rimi.imi.bg.ac.rs/handle/123456789/952
dc.description.abstractMyeloproliferative neoplasms (MPNs) are developing resistance to therapy by JAK1/2 inhibitor ruxolitinib. 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-6 (IL-6) in MPN granulocytes and JAK2V617F mutated human erythroleukemia (HEL) cells. We found that JAK1/2 or JAK2 inhibition prevented the IL-6 activation of STAT3 and AKT pathways in polycythemia vera and HEL cells. Further, we showed that these inhibitors also blocked the IL-6 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 JAK2V617F positive granulocytes. Regarding a cell cycle, we found that IL-6 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-6 augmentation of MPN granulocytes frequency in the S phase of the cell cycle (up to 2.9 fold). The inflammatory stimulation induces a cross-talk between the proliferation linked pathways, where JAK1/2 inhibition is compensated by the activation of the ERK1/2 pathway during IL-6 stimulation of DNA replication.en
dc.publisherWiley, Hoboken
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/175053/RS//
dc.relationSwiss National Science Foundation through Joint research project (SCOPES) [IZ73Z0 152420/1]
dc.relationIntramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, USA
dc.rightsopenAccess
dc.sourceCell Biology International
dc.subjectcell cycleen
dc.subjectERK1/2 signalingen
dc.subjectinflammationen
dc.subjectJAK1/2 inhibitionen
dc.subjectmyeloproliferative neoplasmen
dc.titleIL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signalingen
dc.typearticle
dc.rights.licenseARR
dc.citation.epage206
dc.citation.issue2
dc.citation.other43(2): 192-206
dc.citation.rankM23
dc.citation.spage192
dc.citation.volume43
dc.identifier.doi10.1002/cbin.11084
dc.identifier.fulltexthttp://rimi.imi.bg.ac.rs/bitstream/id/749/949.pdf
dc.identifier.pmid30571852
dc.identifier.scopus2-s2.0-85059636389
dc.identifier.wos000456803100012
dc.type.versionpublishedVersion


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