{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:58:36Z","timestamp":1779256716479,"version":"3.51.4"},"reference-count":20,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,7,18]],"date-time":"2021-07-18T00:00:00Z","timestamp":1626566400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA97274"],"award-info":[{"award-number":["CA97274"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European J of Haematology"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Despite the unprecedented success of ibrutinib in lymphoma therapy, the development of ibrutinib resistance due to acquired <jats:italic>BTK<\/jats:italic> or <jats:italic>PLC\u03b32<\/jats:italic> mutations has become a new clinical problem. However, not all resistance is mediated by these mutations and these mechanisms are poorly understood due to a lack of study tools that truly recapitulate this clinical scenario.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We established a novel patient\u2010derived ibrutinib\u2010resistant mantle cell lymphoma (MCL) line named MCIR1. Using immunological, molecular, and cytogenetic approaches, we comprehensively characterized MCIR1 and further demonstrated its utility in the study of resistance mechanisms and treatments to overcome this resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that MCIR1 is a <jats:italic>bona fide<\/jats:italic> ibrutinib\u2010resistant MCL cell line with normal BTK\u2010\/PLC\u03b32 but ibrutinib\u2010resistant ERK1\/2 and AKT1 signaling. RNA\u2010Seq analysis revealed a robust non\u2010canonical NF\u2010kB signaling that drives the ibrutinib resistance. We also demonstrate the potential utility of a MCIR1\u2010based cell and mouse model for the discovery of new treatments to overcome BTK inhibitor resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We have established the first patient\u2010derived ibrutinib\u2010resistant MCL cell line MCIR1 that lacks <jats:italic>BTK<\/jats:italic> or <jats:italic>PLC\u03b32<\/jats:italic> mutations but exhibits a hyperactive non\u2010canonical NF\u2010kB pathway. We further demonstrate its utility in the discovery and validation of new drugs to overcome this resistance.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ejh.13682","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T19:05:06Z","timestamp":1625252706000},"page":"458-465","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["MCIR1: A patient\u2010derived mantle cell lymphoma line for discovering new treatments for ibrutinib resistance"],"prefix":"10.1111","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8043-2177","authenticated-orcid":false,"given":"Xiaosheng","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Medicine Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin E.","family":"Nowakowski","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jithma P.","family":"Abeykoon","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Manske","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary J.","family":"Stenson","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael M.","family":"Timm","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Curtis A.","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel L.","family":"Van Dyke","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surendra","family":"Dasari","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Research Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas E.","family":"Witzig","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine Mayo Clinic Rochester MN 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