{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:22:47Z","timestamp":1791296567530,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2013,11,17]],"date-time":"2013-11-17T00:00:00Z","timestamp":1384646400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Aberrant\n                    <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>\n                    2 signalling plays a central role in myeloproliferative neoplasms (\n                    <jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content>\n                    ).\n                    <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>\n                    2 inhibitors have proven to be clinically efficacious, however, they are not mutation\u2010specific and competent enough to suppress neoplastic clonal haematopoiesis. We hypothesized that, by simultaneously targeting multiple activated signalling pathways,\n                    <jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content>\n                    could be more effectively treated. To this end we investigated the efficacy of\n                    <jats:styled-content style=\"fixed-case\">BEZ<\/jats:styled-content>\n                    235, a dual PI3K\/\n                    <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>\n                    inhibitor, alone and in combination with the\n                    <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>\n                    1\/\n                    <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>\n                    2 inhibitor ruxolitinib, in different preclinical models of\n                    <jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content>\n                    . Single\u2010agent\n                    <jats:styled-content style=\"fixed-case\">BEZ<\/jats:styled-content>\n                    235 inhibited the proliferation and induced cell cycle arrest and apoptosis of mouse and human\n                    <jats:italic>JAK2<\/jats:italic>\n                    V617F mutated cell lines at concentrations significantly lower than those required to inhibit the wild\u2010type counterpart, and preferentially prevented colony formation from\n                    <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>\n                    2V617F knock\u2010in mice and patients' progenitor cells compared with normal ones. Co\u2010treatment of\n                    <jats:styled-content style=\"fixed-case\">BEZ<\/jats:styled-content>\n                    235 and ruxolitinib produced significant synergism in all these\n                    <jats:italic>in\u2010vitro<\/jats:italic>\n                    models. Co\u2010treatment was also more effective than single drugs in reducing the extent of disease and prolonging survival of immunodeficient mice injected with\n                    <jats:italic>JAK2<\/jats:italic>\n                    V617F\u2010mutated Ba\/F3\u2010\n                    <jats:styled-content style=\"fixed-case\">EPOR<\/jats:styled-content>\n                    cells and in reducing spleen size, decreasing reticulocyte count and improving spleen histopathology in conditional\n                    <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>\n                    2V617F knock\u2010in mice. In conclusion, combined inhibition of PI3K\/\n                    <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>\n                    and\n                    <jats:styled-content style=\"fixed-case\">JAK<\/jats:styled-content>\n                    2 signalling may represent a novel therapeutic strategy in\n                    <jats:styled-content style=\"fixed-case\">MPN<\/jats:styled-content>\n                    .\n                  <\/jats:p>","DOI":"10.1111\/jcmm.12162","type":"journal-article","created":{"date-parts":[[2013,11,17]],"date-time":"2013-11-17T21:29:39Z","timestamp":1384723779000},"page":"1385-1396","source":"Crossref","is-referenced-by-count":98,"title":["Co\u2010targeting the PI3K\/\n                    <scp>mTOR<\/scp>\n                    and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms"],"prefix":"10.1111","volume":"17","author":[{"given":"Niccol\u00f2","family":"Bartalucci","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Tozzi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Bogani","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giada","family":"Rotunno","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Luc","family":"Villeval","sequence":"additional","affiliation":[{"name":"Inserm, U.1009 Institut Gustave Roussy and Universit\u00e9 Paris XI Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro M.","family":"Vannucchi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Florence Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,11,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.20009"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.42.0240"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-292102"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2210"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030270"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-01-131664"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-01-135897"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.161"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197406132902419"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-10-054940"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.006817"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.05.015"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-12-257063"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-12-4824"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.31.8436"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-04-218842"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1298"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-04-214957"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3264"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.269"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.32.8021"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1002028"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110557"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110556"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03546"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-2210"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2405043"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-04-215848"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2009.07870.x"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2012.09246.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-330563"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa051113"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-04-083501"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-10-0053"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-04-498956"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10161"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1947"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0027509"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054826"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI42442"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-1541"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11303"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2405049"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-05-222133"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1879"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.3109\/10409238.2011.618113"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2003.11.003"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2664"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2006.11.012"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.167"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0862"}],"container-title":["Journal of Cellular and Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjcmm.12162","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.12162","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jcmm.12162","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.12162","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T04:56:36Z","timestamp":1696222596000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jcmm.12162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,11]]},"references-count":51,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2013,11]]}},"alternative-id":["10.1111\/jcmm.12162"],"URL":"https:\/\/doi.org\/10.1111\/jcmm.12162","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718179867.793516215","asserted-by":"object"}]},"ISSN":["1582-1838","1582-4934"],"issn-type":[{"value":"1582-1838","type":"print"},{"value":"1582-4934","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,11]]}}}