{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T08:04:30Z","timestamp":1780733070222,"version":"3.54.1"},"reference-count":64,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,13]],"date-time":"2024-07-13T00:00:00Z","timestamp":1720828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["P01-CA108671"],"award-info":[{"award-number":["P01-CA108671"]}]},{"name":"National Cancer Institute","award":["IG23525"],"award-info":[{"award-number":["IG23525"]}]},{"name":"Italian Cancer Research Association","award":["P01-CA108671"],"award-info":[{"award-number":["P01-CA108671"]}]},{"name":"Italian Cancer Research Association","award":["IG23525"],"award-info":[{"award-number":["IG23525"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Studies conducted on animal models have identified several therapeutic targets for myelofibrosis, the most severe of the myeloproliferative neoplasms. Unfortunately, many of the drugs which were effective in pre-clinical settings had modest efficacy when tested in the clinic. This discrepancy suggests that treatment for this disease requires combination therapies. To rationalize possible combinations, the efficacy in the Gata1low model of drugs currently used for these patients (the JAK1\/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-\u03b2 (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-\u03b2) signaling and TGF-\u03b2 trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1\/2). The comparison was carried out by expressing the endpoints, which had either already been published or had been retrospectively obtained for this study, as the fold change of the values in the corresponding vehicles. In this model, only Ruxolitinib was found to decrease spleen size, only Aplidin and SB431542\/AVID200 increased platelet counts, and with the exception of AVID200, all the inhibitors reduced fibrosis and microvessel density. The greatest effects were exerted by Reparixin, which also reduced TGF-\u03b2 content. None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1\/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-\u03b2 or CXCL1).<\/jats:p>","DOI":"10.3390\/ijms25147703","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T15:17:06Z","timestamp":1721056626000},"page":"7703","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Variation in the Traits Ameliorated by Inhibitors of JAK1\/2, TGF-\u03b2, P-Selectin, and CXCR1\/CXCR2 in the Gata1low Model Suggests That Myelofibrosis Should Be Treated by These Drugs in Combination"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4082-4675","authenticated-orcid":false,"given":"Francesca","family":"Gobbo","sequence":"first","affiliation":[{"name":"Department of Veterinary Medical Sciences, Alma Mater Studiorum University, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7811-242X","authenticated-orcid":false,"given":"Fabrizio","family":"Martelli","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Di Virgilio","sequence":"additional","affiliation":[{"name":"National Center for Drug Research and Evaluation, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3683-0232","authenticated-orcid":false,"given":"Elena","family":"Demaria","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Alma Mater Studiorum University, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6405-3484","authenticated-orcid":false,"given":"Giuseppe","family":"Sarli","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medical Sciences, Alma Mater Studiorum University, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Rita","family":"Migliaccio","sequence":"additional","affiliation":[{"name":"Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA"},{"name":"Institute of Nanotechnology, National Research Council (Cnr-NANOTEC), c\/o Campus Ecotekne, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/ajh.26857","article-title":"Primary Myelofibrosis: 2023 Update on Diagnosis, Risk-stratification, and Management","volume":"98","author":"Tefferi","year":"2023","journal-title":"Am. 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