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We examined the CLL cells of seven such patients (CLL1-7) and found each had high-level expression of ROR1. By examining the CLL cells from such patients prior to therapy at SC1 and then more than 1 year later (Sample Collection 2 (SC2)), when they had progressive increases in MRD despite continued venetoclax therapy, we found the levels of ROR1 expressed on CLL cells at SC2 were significantly higher than that on CLL cells collected at SC1. At SC2, we also observed upregulation of genes induced by Wnt5a-induced ROR1 signaling, including <jats:italic>BCL2L1<\/jats:italic>. Transduction of the CLL-cell-line MEC1 to express <jats:italic>ROR1<\/jats:italic> enhanced expression of target genes induced by ROR1-signaling, increased expression of BCL-XL, and enhanced resistance to venetoclax, even in MEC1 made to express mutant forms of <jats:italic>BCL2<\/jats:italic>, which are associated with venetoclax resistance. Treatment of primary CLL cells with Wnt5a also increased their resistance to venetoclax, an effect that could be inhibited by the anti-ROR1 mAb (UC-961, zilovertamab). Collectively, these studies indicate that Wnt5a-induced ROR1-signaling can enhance resistance to venetoclax therapy.<\/jats:p>","DOI":"10.1038\/s41375-022-01543-y","type":"journal-article","created":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T18:04:02Z","timestamp":1649873042000},"page":"1609-1618","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["High expression level of ROR1 and ROR1-signaling associates with venetoclax resistance in chronic lymphocytic leukemia"],"prefix":"10.1038","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6060-6106","authenticated-orcid":false,"given":"Emanuela M.","family":"Ghia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Z.","family":"Rassenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Y.","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Quijada-\u00c1lamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvin","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"George F.","family":"Widhopf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0064-4549","authenticated-orcid":false,"given":"Thomas J.","family":"Kipps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,13]]},"reference":[{"key":"1543_CR1","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nm.3048","volume":"19","author":"AJ Souers","year":"2013","unstructured":"Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. 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Blood. 2020;135:2192\u20135.","journal-title":"Blood"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01543-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01543-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01543-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T08:06:15Z","timestamp":1654157175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-022-01543-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,13]]},"references-count":50,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["1543"],"URL":"https:\/\/doi.org\/10.1038\/s41375-022-01543-y","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,13]]},"assertion":[{"value":"25 October 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 April 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"EMG, LZR, MQA, GFW, and EC have no conflict of interest. Zilovertamab was developed by TJK and his laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock and research funding. MYC and TJK also have received research funding from Pharmacyclics and AbbVie.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}