{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T16:17:20Z","timestamp":1773937040786,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:00:00Z","timestamp":1771200000000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004721","name":"University of Tokyo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004721","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Resistance to tyrosine kinase inhibitors (TKIs) remains a major challenge in breakpoint cluster region (BCR)::Abelson 1 (ABL1)\u2010driven leukaemias. Asciminib offers a novel therapeutic option; however, resistance continues to emerge. We hypothesised that targeting proteostasis and epigenetic regulation with bortezomib and panobinostat could eliminate TKI\u2010refractory cells via TKI\u2010independent mechanisms. We profiled parental and TKI\u2010resistant chronic myelogenous leukaemia (CML) and Ba\/F3 models. Viability, cytotoxicity, and caspase\u20103\/7 activity were assessed following single\u2010agent treatment with asciminib, ponatinib, bortezomib, or panobinostat. The effects of the bortezomib\u2013panobinostat combination on colony formation, mitochondrial membrane potential, and apoptosis were evaluated. Asciminib showed reduced potency in resistant models and a right\u2010shifted dose\u2013response curve in T315I cells, whereas ponatinib retained activity across BCR::ABL1 variants. Bortezomib and panobinostat induced low\u2010nanomolar cytotoxicity and robust caspase\u20103\/7 activation in resistant lines. The combination of bortezomib and panobinostat showed modest trends toward reduced cell viability and increased cytotoxicity and caspase\u20103\/7 activity, especially in TKI\u2010resistant cells. The combination suppressed clonogenic growth and triggered apoptosis in resistant cells. Co\u2010inhibition of proteasomes and histone deacetylases eliminates TKI\u2010refractory BCR::ABL1\u2010driven leukaemia cells by inducing mitochondrial apoptosis and loss of clonogenic potential. These findings indicate a clinically actionable, TKI\u2010independent strategy for the salvage treatment of multidrug\u2010resistant CML.<\/jats:p>","DOI":"10.1111\/jcmm.71053","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T21:21:23Z","timestamp":1771276883000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Proteasome and Histone Deacetylase Inhibition Overcomes Tyrosine Kinase Inhibitor Resistance in Breakpoint Cluster Region: Abelson 1\u2010Driven Leukaemia Cell Lines"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2727-658X","authenticated-orcid":false,"given":"Seiichi","family":"Okabe","sequence":"first","affiliation":[{"name":"Department of Hematology Tokyo Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiichiro","family":"Yoshizawa","sequence":"additional","affiliation":[{"name":"Department of Hematology Tokyo Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuya","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Hematology Tokyo Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiko","family":"Gotoh","sequence":"additional","affiliation":[{"name":"Department of Hematology Tokyo Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daigo","family":"Akahane","sequence":"additional","affiliation":[{"name":"Department of Hematology Tokyo Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2025.0220"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0780-6"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14143300"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01055-9"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-05-431379"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-025-02185-0"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2024.116254"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071898"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12279"},{"issue":"2","key":"e_1_2_10_11_1","first-page":"166","article-title":"Histone Deacetylase Inhibitors: Molecular Mechanisms of Action and Clinical Trials as Anti\u2010Cancer Drugs","volume":"3","author":"Kim H. 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