{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:48:10Z","timestamp":1791830890820,"version":"4.3.4"},"reference-count":59,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The BCR-ABL1 chimeric oncoprotein plays a pivotal role in the pathogenesis of Chronic Myeloid Leukemia (CML) as its constitutive kinase activity transforms the hematopoietic stem cell, promoting pro-survival signaling. We and others have previously shown that the manipulation of BCR-ABL1 catalytic activity modulates its intracellular localization, thereby transforming the culprit of CML into a pro-apoptotic protein that selectively kills leukemic cells. Here, we investigated the role of the BCR coiled-coil and C2 domains on BCR-ABL1 intracellular localization and leukemogenic potential. We performed a bioinformatic analysis that identified two putative nuclear localization signals (NLSs) in BCR. Using recombinant DNA strategies, we generated multiple BCR and BCR-ABL1 mutants that were ectopically expressed in human cells. The intracellular localization of each construct was analyzed by immunofluorescence, while their biological activity was investigated employing proliferation and transforming assays. We show that BCR displays two nuclear localization signals functionally inactivated by the coiled-coil and C2 domains. The removal of these regions reactivated the nuclear migration of both BCR and BCR-ABL1 mutants. Moreover, BCR-ABL1 constructs devoid of the coiled-coil and C2 domains displayed reduced transforming potential in Ba\/F3 cells and in primary human CD34+ progenitors. Finally, we demonstrate that the deletion of the C2 domain compromises TKI efficacy. Our findings identify two nuclear localization signals in the BCR sequence that are functionally suppressed by the coiled-coil and C2 domains. Targeting these regions may provide additional therapeutic strategies to manipulate both BCR-ABL1 intracellular localization and kinase activity.<\/jats:p>","DOI":"10.3390\/ijms26146591","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T12:46:33Z","timestamp":1752237993000},"page":"6591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Coiled Coil and C2 Domains Modulate BCR Localization and BCR-ABL1 Compartmentalization, Transforming Activity and TKI Responsiveness"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5896-8573","authenticated-orcid":false,"given":"Michele","family":"Massimino","sequence":"first","affiliation":[{"name":"Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy"},{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Stella","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-8266","authenticated-orcid":false,"given":"Chiara","family":"Romano","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Buffa","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8012-5134","authenticated-orcid":false,"given":"Elena","family":"Tirr\u00f2","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Drago","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Manzella","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1044-1008","authenticated-orcid":false,"given":"Cristina","family":"Tomarchio","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"},{"name":"Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, 95127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7948-3580","authenticated-orcid":false,"given":"Silvia Rita","family":"Vitale","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Di Raimondo","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy"},{"name":"Division of Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Vigneri","sequence":"additional","affiliation":[{"name":"Center of Experimental Oncology and Hematology, A.O.U. Policlinico \u201cG. Rodolico-S. Marco\u201d, 95123 Catania, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95100 Catania, Italy"},{"name":"Division of Oncology, Humanitas Istituto Clinico Catanese, 95045 Misterbianco, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1158\/1078-0432.CCR-10-1613","article-title":"Molecular pathways: BCR-ABL","volume":"18","author":"Cilloni","year":"2012","journal-title":"Clin. 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