{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:40:20Z","timestamp":1779928820117,"version":"3.53.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Therapy of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) targeting the\n                      <jats:italic>BCR::ABL1<\/jats:italic>\n                      kinase has become a paradigm for precision oncology. Despite the tremendous success of this strategy, with an overall long-term survival rate of 83%, approximately 25% of CML patients experience therapy failure within 5\u00a0years of treatment. TKI resistance is multifaceted, involving mutations in\n                      <jats:italic>BCR::ABL1<\/jats:italic>\n                      , but also BCR::ABL1-independent mechanisms. Among them, deregulation of cell adhesion and motility of CML cells has been observed in TKI-resistance. The extracellular matrix protein fibronectin 1 (FN1) has been shown to be deregulated in solid tumors promoting proliferation and metastasis. However, the role of FN1 in hematopoietic neoplasms remains to be fully elucidated. The aim of our study was to gain deeper insights into the role of FN1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      <jats:italic>FN1<\/jats:italic>\n                      mRNA and protein levels were analyzed using qPCR and immunoblotting. Transfection was performed using nucleofection or stable transfection, followed by analyses of cell number, proliferation and viability. Cell adhesion was assessed using Matrigel-coated surfaces, and FN1 localization was analyzed using immunofluorescence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      FN1 levels were significantly downregulated in CML cell lines resistant against BCR::ABL1 inhibitors\n                      <jats:italic>in vitro<\/jats:italic>\n                      . SiRNA-mediated\n                      <jats:italic>FN1<\/jats:italic>\n                      knockdown reduced the cell\u2019s susceptibility to all generations of TKIs employed in treatment of CML, including asciminib. In contrast, the restoration of\n                      <jats:italic>FN1<\/jats:italic>\n                      expression in TKI-resistant cells re-sensitized the cells to TKI treatment. This effect was also observed in K-562 cells that intrinsically harbor the\n                      <jats:italic>BCR::ABL1<\/jats:italic>\n                      mutation p. E255K (\u221235.2%,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001), as well as in K-562 and Ba\/F3 cells after stable transfection of the BCR::ABL1 wild-type or the p. T315I gatekeeper mutation. Clinically, deregulation of\n                      <jats:italic>FN1<\/jats:italic>\n                      was also observed in peripheral blood cells derived from CML patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data indicate that FN1 may serve as a potential therapeutic target to address TKI resistance or as a suitable biomarker for the treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2025.1725857","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T06:25:57Z","timestamp":1766125557000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Association of fibronectin 1 deregulation with tyrosine kinase inhibitor resistance in chronic myeloid leukemia"],"prefix":"10.3389","volume":"13","author":[{"given":"Lina","family":"Tiedemann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivahari Prasad","family":"Gorantla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philine","family":"Ahlf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie Sophie","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Pott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merit","family":"Litterst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicki","family":"Waetzig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga","family":"Nagel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Ruemenapp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolas","family":"von Bubnoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingolf","family":"Cascorbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meike","family":"Kaehler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1182\/blood-2013-05-501569","article-title":"European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013","volume":"122","author":"Baccarani","year":"2013","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/leu.2010.238","article-title":"Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia","volume":"25","author":"Bixby","year":"2011","journal-title":"Leukemia"},{"key":"B3","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1124\/mol.119.116590","article-title":"Alternative polyadenylation of ABC transporters of the C-Family (ABCC1, ABCC2, ABCC3) and implications on posttranscriptional Micro-RNA regulation","volume":"97","author":"Bruhn","year":"2020","journal-title":"Mol. Pharmacol."},{"key":"B4","first-page":"100","article-title":"Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative","volume":"56","author":"Buchdunger","year":"1996","journal-title":"Cancer Research"},{"key":"B5","doi-asserted-by":"publisher","first-page":"4010","DOI":"10.1182\/blood-2003-12-4111","article-title":"The biology of CML blast crisis","volume":"103","author":"Calabretta","year":"2004","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.canlet.2015.01.041","article-title":"Fibronectin promotes cell proliferation and invasion through mTOR signaling pathway activation in gallbladder cancer","volume":"360","author":"Cao","year":"2015","journal-title":"Cancer Lett."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e52233","DOI":"10.1371\/journal.pone.0052233","article-title":"Gleevec, an Abl family inhibitor, produces a profound change in cell shape and migration","volume":"8","author":"Chen","year":"2013","journal-title":"PLoS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e76989","DOI":"10.1371\/journal.pone.0076989","article-title":"Biological, functional and genetic characterization of bone marrow-derived mesenchymal stromal cells from pediatric patients affected by acute lymphoblastic leukemia","volume":"8","author":"Conforti","year":"2013","journal-title":"PLoS One"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1038\/sj.leu.2402179","article-title":"Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR\/ABL inhibition, cytotoxic drugs, and gamma-irradiation","volume":"15","author":"Damiano","year":"2001","journal-title":"Leukemia"},{"key":"B10","doi-asserted-by":"publisher","first-page":"86","DOI":"10.33590\/emjoncol\/10311536","article-title":"The importance of mutational analyses in chronic myeloid leukaemia for treatment choice","volume":"4","author":"De Lavallade","year":"2016","journal-title":"Eur. Med. J. Oncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3343","DOI":"10.1182\/blood.v96.10.3343","article-title":"The molecular biology of chronic myeloid leukemia","volume":"96","author":"Deininger","year":"2000","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/nm0596-561","article-title":"Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells","volume":"2","author":"Druker","year":"1996","journal-title":"Nat. Medicine"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1002\/jcp.31048","article-title":"Shielding and nurturing: Fibronectin as a modulator of cancer drug resistance","volume":"238","author":"Farooq","year":"2023","journal-title":"J. Cell Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/1471-2407-13-60","article-title":"SPARC expression in CML is associated to imatinib treatment and to inhibition of leukemia cell proliferation","volume":"13","author":"Giallongo","year":"2013","journal-title":"BMC Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"4600","DOI":"10.1182\/blood-2009-07-236133","article-title":"Oncogenic JAK2V617F requires an intact SH2-like domain for constitutive activation and induction of a myeloproliferative disease in mice","volume":"116","author":"Gorantla","year":"2010","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1056\/NEJMoa1609324","article-title":"Long-term outcomes of imatinib treatment for chronic myeloid leukemia","volume":"376","author":"Hochhaus","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1038\/s41375-020-0776-2","article-title":"European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia","volume":"34","author":"Hochhaus","year":"2020","journal-title":"Leukemia"},{"key":"B18","doi-asserted-by":"publisher","first-page":"696960","DOI":"10.3389\/fphar.2021.696960","article-title":"Pharmacogenomics of impaired tyrosine kinase inhibitor response: lessons learned from chronic myelogenous leukemia","volume":"12","author":"Kaehler","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"92018","DOI":"10.18632\/oncotarget.21272","article-title":"MicroRNA-212\/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells","volume":"8","author":"Kaehler","year":"2017","journal-title":"Oncotarget"},{"key":"B20","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.exphem.2021.05.006","article-title":"ZFP36L1 plays an ambiguous role in the regulation of cell expansion and negatively regulates CDKN1A in chronic myeloid leukemia cells","volume":"99","author":"Kaehler","year":"2021","journal-title":"Exp. Hematol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"144","DOI":"10.3892\/or.2022.8355","article-title":"Genome-wide expression and methylation analyses reveal aberrant cell adhesion signaling in tyrosine kinase inhibitor-resistant CML cells","volume":"48","author":"Kaehler","year":"2022","journal-title":"Oncol. Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1200897","DOI":"10.3389\/fonc.2023.1200897","article-title":"Clonal evolution in tyrosine kinase inhibitor-resistance: lessons from in vitro-models","volume":"13","author":"Kaehler","year":"2023","journal-title":"Front. Oncol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.3324\/haematol.2014.113852","article-title":"A hostel for the hostile: the bone marrow niche in hematologic neoplasms","volume":"100","author":"Krause","year":"2015","journal-title":"Haematologica"},{"key":"B24","doi-asserted-by":"publisher","first-page":"9535","DOI":"10.1038\/s41598-017-10373-3","article-title":"Adhesion to stromal cells mediates imatinib resistance in chronic myeloid leukemia through ERK and BMP signaling pathways","volume":"7","author":"Kumar","year":"2017","journal-title":"Sci. Rep."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1038\/s41375-020-0866-1","article-title":"Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia","volume":"34","author":"Kumar","year":"2020","journal-title":"Leukemia"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1242\/jcs.03430","article-title":"Bcr-Abl induces abnormal cytoskeleton remodeling, beta1 integrin clustering and increased cell adhesion to fibronectin through the Abl interactor 1 pathway","volume":"120","author":"Li","year":"2007","journal-title":"J. Cell Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"27","DOI":"10.3390\/cells9010027","article-title":"Fibronectin in cancer: friend or foe","volume":"9","author":"Lin","year":"2019","journal-title":"Cells"},{"key":"B28","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1182\/blood.v45.3.321.bloodjournal453321","article-title":"Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome","volume":"45","author":"Lozzio","year":"1975","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/ejh.13408","article-title":"The multi-tyrosine kinase inhibitor ponatinib for chronic myeloid leukemia: real-World data","volume":"105","author":"Luciano","year":"2020","journal-title":"Eur. J. Haematol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1055\/s-0042-1757911","article-title":"A retrospective analysis of BCR-ABL1 kinase domain mutations in the frontline drug intolerant or resistant chronic myeloid leukemia patients: an Indian experience from a high-end referral laboratory","volume":"13","author":"Majumdar","year":"2024","journal-title":"South Asian J. Cancer"},{"key":"B31","first-page":"335","article-title":"Bi-phenotypic t(9;22)-positive leukemia cell lines from a patient with acute leukemia: NALM-20, established at the onset; and NALM-21, NALM-22 and NALM-23, established after relapse","volume":"4","author":"Matsuo","year":"1991","journal-title":"Hum. Cell"},{"key":"B32","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/sj.bjc.6605154","article-title":"Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion","volume":"101","author":"Meng","year":"2009","journal-title":"Br. J. Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"7519","DOI":"10.1158\/1078-0432.CCR-09-1068","article-title":"Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia","volume":"15","author":"Milojkovic","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"117","DOI":"10.3390\/cells10010117","article-title":"Chronic myeloid leukemia: a model disease of the past, present and future","volume":"10","author":"Minciacchi","year":"2021","journal-title":"Cells"},{"key":"B35","doi-asserted-by":"publisher","first-page":"113519","DOI":"10.1016\/j.biopha.2022.113519","article-title":"SPARC in hematologic malignancies and novel technique for hematological disease with its abnormal expression","volume":"153","author":"Nian","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e107367","DOI":"10.1371\/journal.pone.0107367","article-title":"Real-time analysis of imatinib- and dasatinib-induced effects on chronic myelogenous leukemia cell interaction with fibronectin","volume":"9","author":"Obr","year":"2014","journal-title":"PLoS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.1182\/blood-2007-03-066936","article-title":"Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia","volume":"110","author":"O\u2019hare","year":"2007","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"3861","DOI":"10.1242\/jcs.00059","article-title":"Fibronectin at a glance","volume":"115","author":"Pankov","year":"2002","journal-title":"J. Cell Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.3390\/cancers15041045","article-title":"Toxicity of asciminib in real clinical practice: analysis of side effects and cross-toxicity with tyrosine kinase inhibitors","volume":"15","author":"Perez-Lamas","year":"2023","journal-title":"Cancers"},{"key":"B40","doi-asserted-by":"publisher","first-page":"3496","DOI":"10.1182\/blood-2006-07-036012","article-title":"Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia","volume":"109","author":"Picard","year":"2007","journal-title":"Blood"},{"key":"B41","article-title":"Image J","author":"Rasband","year":"1997"},{"key":"B42","doi-asserted-by":"publisher","first-page":"8120","DOI":"10.1021\/acs.jmedchem.8b01040","article-title":"Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1","volume":"61","author":"Schoepfer","year":"2018","journal-title":"J. Med. Chem."},{"key":"B43","first-page":"822","article-title":"Human chronic myeloid leukemic cell line with positive Philadelphia chromosome exhibits megakaryocytic and erythroid characteristics","volume":"15","author":"Seigneurin","year":"1987","journal-title":"Exp. Hematol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s13046-021-01908-8","article-title":"Fibronectin as a multiregulatory molecule crucial in tumor matrisome: from structural and functional features to clinical practice in oncology","volume":"40","author":"Spada","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"S39","DOI":"10.1016\/j.leukres.2003.10.007","article-title":"Molecular mechanisms of resistance of leukemia to imatinib mesylate","volume":"28","author":"Tauchi","year":"2004","journal-title":"Leuk. Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/1755-1536-4-21","article-title":"Plasma and cellular fibronectin: distinct and independent functions during tissue repair","volume":"4","author":"To","year":"2011","journal-title":"Fibrogenes. Tissue Repair"},{"key":"B47","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1097\/FPC.0b013e328350012b","article-title":"MicroRNA profiling in K-562 cells under imatinib treatment: influence of miR-212 and miR-328 on ABCG2 expression","volume":"22","author":"Turrini","year":"2012","journal-title":"Pharmacogenet Genomics"},{"key":"B48","doi-asserted-by":"publisher","first-page":"5974","DOI":"10.1002\/jcb.27885","article-title":"Retinoic acid-induced survival effects in SH-SY5Y neuroblastoma cells","volume":"120","author":"Waetzig","year":"2019","journal-title":"J. Cell Biochem."},{"key":"B49","doi-asserted-by":"publisher","first-page":"674","DOI":"10.7150\/jca.16901","article-title":"Fibronectin: how its aberrant expression in tumors may improve therapeutic targeting","volume":"8","author":"Wang","year":"2017","journal-title":"J. Cancer"},{"key":"B50","doi-asserted-by":"publisher","first-page":"2717","DOI":"10.3390\/cells9122717","article-title":"Fibronectin and its receptors in hematopoiesis","volume":"9","author":"Wirth","year":"2020","journal-title":"Cells"},{"key":"B51","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/s12885-021-07875-9","article-title":"Fibronectin mediates activation of stromal fibroblasts by SPARC in endometrial cancer cells","volume":"21","author":"Yoshida","year":"2021","journal-title":"BMC Cancer"},{"key":"B52","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1002\/cbin.10184","article-title":"Fibronectin promotes migration and invasion of ovarian cancer cells through up-regulation of FAK-PI3K\/Akt pathway","volume":"38","author":"Yousif","year":"2014","journal-title":"Cell Biol. Int."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.3324\/haematol.2018.212027","article-title":"Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia","volume":"105","author":"Yu","year":"2020","journal-title":"Haematologica"},{"key":"B54","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/j.ccr.2014.07.006","article-title":"BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia","volume":"26","author":"Zabriskie","year":"2014","journal-title":"Cancer Cell"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1725857\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T06:25:59Z","timestamp":1766125559000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2025.1725857\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,19]]},"references-count":54,"alternative-id":["10.3389\/fcell.2025.1725857"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2025.1725857","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,19]]},"article-number":"1725857"}}