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However, resistance of CML<\/jats:styled-content> stem cells to TKI<\/jats:styled-content> may contribute to the 50% relapse rate observed after TKI<\/jats:styled-content> discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM<\/jats:styled-content>), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr\u2010Abl1 protein and activity levels while maintaining proliferative potential. Using quantitative phosphoproteomic analysis of these IM<\/jats:styled-content>\u2010resistant cells, we have now identified significant upregulation of tumor progression locus (Tpl2), also known as cancer Osaka thyroid (COT<\/jats:styled-content>1) kinase or Map3k8. Overexpression of Tpl2 in IM<\/jats:styled-content>\u2010resistant cells was accompanied by elevated activities of Src family kinases (SFK<\/jats:styled-content>s) and NF<\/jats:styled-content>\u2010\u03baB, MEK<\/jats:styled-content>\u2010ERK<\/jats:styled-content> signaling. CD<\/jats:styled-content>34+ cells isolated from the bone marrow of patients with CML<\/jats:styled-content> and exposed to IM<\/jats:styled-content>in\u00a0vitro<\/jats:italic> showed increased MAP<\/jats:styled-content>3K8<\/jats:italic> transcript levels. Dasatinib (SFK<\/jats:styled-content> inhibitor), U0126 (MEK<\/jats:styled-content> inhibitor), and PS<\/jats:styled-content>\u20101145 (I\u03baB kinase (IKK<\/jats:styled-content>) inhibitor) used in combination resulted in elimination of 65% of IM<\/jats:styled-content>\u2010resistant cells and reduction in the colony\u2010forming capacity of CML CD<\/jats:styled-content>34+ cells in methylcellulose assays by 80%. In addition, CML CD<\/jats:styled-content>34+ cells cultured with the combination of inhibitors showed reduced MAP<\/jats:styled-content>3K8<\/jats:italic> transcript levels. Overall, our data indicate that elevated Tpl2 protein and transcript levels are associated with resistance to IM<\/jats:styled-content> and that combined inhibition of SFK<\/jats:styled-content>, MEK<\/jats:styled-content>, and NF<\/jats:styled-content>\u2010\u03baB signaling attenuates the survival of IM<\/jats:styled-content>\u2010resistant CML<\/jats:styled-content> cells and CML CD<\/jats:styled-content>34+ cells. Therefore, combination of SFK, MEK, and NF\u2010\u03baB inhibitors may offer a new therapeutic approach to overcome TKI<\/jats:styled-content> resistance in CML<\/jats:styled-content> patients.<\/jats:p>","DOI":"10.1002\/1878-0261.12186","type":"journal-article","created":{"date-parts":[[2018,2,27]],"date-time":"2018-02-27T13:36:43Z","timestamp":1519738603000},"page":"630-647","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK<\/scp>\u2010ERK<\/scp> and NF<\/scp>\u2010\u03baB pathways in a model of chronic myeloid leukemia"],"prefix":"10.1002","volume":"12","author":[{"given":"Anna","family":"Chorzalska","sequence":"first","affiliation":[{"name":"Signal Transduction Lab Division of Hematology\/Oncology Rhode Island Hospital Warren Alpert Medical School Brown University Providence RI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2752-3795","authenticated-orcid":false,"given":"Nagib","family":"Ahsan","sequence":"additional","affiliation":[{"name":"Division of Biology and Medicine COBRE CCRD Proteomics Core Facility Rhode Island Hospital Brown University Providence RI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-6788","authenticated-orcid":false,"given":"R. 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