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Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias. Since recent studies have highlighted the role of miR\u2010146a, a negative regulator of the NF\u2010\u03baB pathway, in the pathogenesis of MF; here we used miR\u2010146a<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> (KO) mice, a MF\u2010like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK\/STAT and\/or NF\u2010\u03baB pathways may reverse the myelofibrotic phenotype of these mice. Specifically, we tested the JAK1\/2 inhibitor, ruxolitinib; the NF\u2010\u03baB inhibitor via IKK\u03b1\/\u03b2, BMS\u2010345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2\/IRAK1), pacritinib. Although all treatments decreased spleen size and partially recovered its architecture, only NF\u2010\u03baB inhibition, either using BMS\u2010345541 (alone or in combination) or pacritinib, resulted in a reduction of extramedullary hematopoiesis, bone marrow (BM) fibrosis and osteosclerosis, along with an attenuation of the exacerbated inflammatory state (via IL\u20101\u03b2 and TNF\u03b1). However, although dual inhibitor improved anemia and reversed thrombocytopenia, the combined therapy worsened anemia by inducing BM hypoplasia. Both therapeutic options reduced NF\u2010\u03baB and JAK\/STAT signaling in a context of JAK2V617F\u2010driven clonal hematopoiesis. Additionally, combined treatment reduced both COL1A1 and IL\u20106 production in an in vitro model mimicking JAK2<\/jats:italic>\u2010driven fibrosis. In conclusion, NF\u2010\u03baB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.<\/jats:p>","DOI":"10.1002\/ajh.27322","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T09:44:13Z","timestamp":1713779053000},"page":"1326-1337","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["miR\u2010146a\u2212\/\u2212<\/sup><\/i> mice model reveals that NF\u2010\u03baB<\/scp> inhibition reverts inflammation\u2010driven<\/scp> myelofibrosis\u2010like phenotype"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3601-4549","authenticated-orcid":false,"given":"Ernesto Jos\u00e9","family":"Cuenca\u2010Zamora","sequence":"first","affiliation":[{"name":"Hematology Department Hospital Universitario Morales\u2010Meseguer, Centro Regional de Hemodonaci\u00f3n, IMIB\u2010Pascual Parrilla, Universidad de Murcia Murcia Spain"},{"name":"CIBERER\u2010ISCIII CB15\/00055 (U765) Murcia Spain"},{"name":"Universidad de Murcia Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8341-592X","authenticated-orcid":false,"given":"Pedro J.","family":"Guijarro\u2010Carrillo","sequence":"additional","affiliation":[{"name":"Hematology Department Hospital Universitario Morales\u2010Meseguer, Centro Regional de Hemodonaci\u00f3n, IMIB\u2010Pascual Parrilla, Universidad de Murcia Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0981-2211","authenticated-orcid":false,"given":"Mar\u00eda J.","family":"L\u00f3pez\u2010Poveda","sequence":"additional","affiliation":[{"name":"Servicio de Anatom\u00eda Patol\u00f3gica, H.U. 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