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Prior studies found that high level expression of MMP-9 in CLL associates more aggressive disease. We find that circulating CLL cells that express high levels the onco-embryonic protein ROR1 express significantly higher levels of MMP-9. Stimulation of CLL cells with Wnt5a could enhance expression and the release of MMP-9 into the culture media and increase the capacity of CLL cells to invade Matrigel in a Boyden-Chamber Assay. Such effects of Wnt5a could not be inhibited by BTK inhibitors such as ibrutinib or zanubrutinib, but could be blocked by zilovertamab, a humanized mAb specific for ROR1. We found that siRNA silencing of NF-\u03baB-p65 or use of an NF-\u03baB inhibitor (CAS 545380-34-5) blocked the capacity of Wnt5a to induce MMP-9 or enhance the invasive capacity of treated CLL cells. Moreover, siRNA directed silencing of <jats:italic>MMP9<\/jats:italic> or treatment with an MMP-9 inhibitor (CAS 1177749-58-4) also blocked the invasive capability of CLL cells induced by Wnt5a. We conclude that Wnt5a-induced ROR1-signaling can induce expression of MMP-9 on CLL cells through activation of NF-\u03baB, thereby enhancing the extravasation and lymphoid-tissue infiltration required for CLL cell trafficking.<\/jats:p>","DOI":"10.1038\/s41375-025-02616-4","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T08:16:08Z","timestamp":1745828168000},"page":"1661-1669","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Wnt5a induces ROR1 dependent NF-\u03baB activation to enhance MMP-9 expression and invasiveness in chronic lymphocytic leukemia"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1271-4428","authenticated-orcid":false,"given":"Md Kamrul","family":"Hasan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George F.","family":"Widhopf II","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6060-6106","authenticated-orcid":false,"given":"Emanuela M.","family":"Ghia","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":[[2025,4,28]]},"reference":[{"key":"2616_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.96","volume":"3","author":"TJ Kipps","year":"2017","unstructured":"Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG, et al. 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