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Mutations within <jats:italic>BCR-ABL1<\/jats:italic>, the oncogene giving rise to chronic myeloid leukemia (CML), lead to resistance to tyrosine kinase inhibitors (TKI), and some are associated with clinically more aggressive disease and worse outcome. Using the retroviral transduction\/transplantation model of CML and human cell lines we faithfully recapitulate accelerated disease course in TKI resistance. We show in various models, that murine and human imatinib-resistant leukemia cells positive for the oncogene <jats:italic>BCR-ABL1<\/jats:italic><jats:sup><jats:italic>T315I<\/jats:italic><\/jats:sup> differ from <jats:italic>BCR-ABL1<\/jats:italic> native (<jats:italic>BCR-ABL1<\/jats:italic>) cells with regards to niche location and specific niche interactions. We implicate a pathway via integrin \u03b23, integrin-linked kinase (ILK) and its role in deposition of the extracellular matrix (ECM) protein fibronectin as causative of these differences. We demonstrate a trend towards a reduced BCR-ABL1<jats:sup>T315I+<\/jats:sup> tumor burden and significantly prolonged survival of mice with BCR-ABL1<jats:sup>T315I+<\/jats:sup> CML treated with fibronectin or an ILK inhibitor in xenogeneic and syngeneic murine transplantation models, respectively. These data suggest that interactions with ECM proteins via the integrin \u03b23\/ILK-mediated signaling pathway in BCR-ABL1<jats:sup>T315I+<\/jats:sup> cells differentially and specifically influence leukemia progression. Niche targeting via modulation of the ECM may be a feasible therapeutic approach to consider in this setting.<\/jats:p>","DOI":"10.1038\/s41375-020-0866-1","type":"journal-article","created":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T12:02:53Z","timestamp":1590062573000},"page":"2087-2101","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia"],"prefix":"10.1038","volume":"34","author":[{"given":"Rahul","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel S.","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Zanetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina R.","family":"Minciacchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Merten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Meister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Niemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina S.","family":"Dietz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"R\u00fcssel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Schn\u00fctgen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minori","family":"Tamai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koshi","family":"Akahane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Inukai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Oellerich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans Michael","family":"Kvasnicka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Pfeifer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck E.","family":"Nicolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Heilemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Van Etten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3603-1119","authenticated-orcid":false,"given":"Daniela S.","family":"Krause","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,21]]},"reference":[{"key":"866_CR1","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrc1590","volume":"5","author":"M Dean","year":"2005","unstructured":"Dean M, Fojo T, Bates S. 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