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Cytotoxic and cytostatic effects of the different compounds were determined in the<jats:italic><jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>2<\/jats:italic><jats:styled-content style=\"fixed-case\">V<\/jats:styled-content>617<jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>\u2010positive cell lines,<jats:styled-content style=\"fixed-case\">HEL<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">B<\/jats:styled-content>a\/<jats:styled-content style=\"fixed-case\">F<\/jats:styled-content>3<jats:sup>JAK2V617F EPOR<\/jats:sup>, and in primary mononuclear and bone marrow<jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>34\u2010positive cells from 19<jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content>patients. Ruxolitinib [50% inhibitory concentration (<jats:styled-content style=\"fixed-case\">IC<\/jats:styled-content><jats:sub>50<\/jats:sub>)<jats:sup>PV<\/jats:sup>\u00a0=\u00a015\u00a0nmol\/l], as well as sorafenib (<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/bjh12308-math-0001.gif\" xlink:title=\"urn:x-wiley:00071048:media:bjh12308:bjh12308-math-0001\"\/>),<jats:styled-content style=\"fixed-case\">KNK<\/jats:styled-content>437 (<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/bjh12308-math-0002.gif\" xlink:title=\"urn:x-wiley:00071048:media:bjh12308:bjh12308-math-0002\"\/>), and perifosine (<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/bjh12308-math-0003.gif\" xlink:title=\"urn:x-wiley:00071048:media:bjh12308:bjh12308-math-0003\"\/>), were able to inhibit proliferation in cell line models and in primary cells from<jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content>patients. Dasatinib,<jats:styled-content style=\"fixed-case\">KNK<\/jats:styled-content>437, and sorafenib showed a strong synergistic effect in combination with ruxolitinib [combination index (<jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>)<jats:sup>PV<\/jats:sup>\u00a0&lt;\u00a00\u00b73]. Western blot confirmed that ruxolitinib blocked<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>, and consequently<jats:styled-content style=\"fixed-case\">STAT<\/jats:styled-content>5 activation, sorafenib inhibited<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">P<\/jats:styled-content>38 and<jats:styled-content style=\"fixed-case\">STAT<\/jats:styled-content>5, dasatinib blocked<jats:styled-content style=\"fixed-case\">SRC<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">STAT<\/jats:styled-content>5, and<jats:styled-content style=\"fixed-case\">KNK<\/jats:styled-content>437 decreased the stability of the<jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>2 protein, reducing its expression. Inhibiting<jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>2\u2010related proliferative pathways has the potential to inhibit cell proliferation in<jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content>s. Furthermore, the combination of ruxolitinib with inhibitors that target these pathways has a strong synergistic effect, which may be due to decreased activation of the common effector,<jats:styled-content style=\"fixed-case\">STAT<\/jats:styled-content>5.<\/jats:p>","DOI":"10.1111\/bjh.12308","type":"journal-article","created":{"date-parts":[[2013,4,5]],"date-time":"2013-04-05T12:07:54Z","timestamp":1365163674000},"page":"667-676","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Inhibition of related<scp>JAK<\/scp>\/<scp>STAT<\/scp>pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm"],"prefix":"10.1111","volume":"161","author":[{"given":"Santiago","family":"Barrio","sequence":"first","affiliation":[{"name":"Haematology Service Hospital Universitario 12 de Octubre Madrid 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