{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:52:08Z","timestamp":1782449528706,"version":"3.54.5"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T00:00:00Z","timestamp":1734912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hematological Oncology"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Contemporary studies of Bruton tyrosine kinase inhibitor (BTKi) resistance focus on mutations in the B\u2010cell receptor (BCR) pathway, but alternative mechanisms of resistance remain undefined. Here, we sought to identify novel predictive markers of acquired resistance to acalabrutinib, a second\u2010generation BTKi, in patients with chronic lymphocytic leukemia (CLL). Clinical samples from 41 patients with relapsed\/refractory or treatment\u2010naive CLL receiving acalabrutinib as part of a clinical trial (NCT02029443) were divided into two groups: those who continued to respond to treatment (NP, <jats:italic>n<\/jats:italic>\u00a0=\u00a023) and those who developed progressive disease on acalabrutinib therapy (PD, <jats:italic>n<\/jats:italic>\u00a0=\u00a018). Peripheral blood mononuclear cells (PBMCs) from the two groups of patients were profiled at baseline (BL) and at a second timepoint (T2) by RNA\u2010seq and flow cytometry. Our findings show a correlation between acquired resistance to acalabrutinib and upregulation of integrin alpha\u20104 (<jats:italic>ITGA4<\/jats:italic>; CD49d), the BCR surface receptor <jats:italic>CD79B<\/jats:italic>, and oncogenes such as <jats:italic>MYC<\/jats:italic>, <jats:italic>LAG3<\/jats:italic>, and <jats:italic>MCL1<\/jats:italic> in CLL cells. High surface expression of CD49d and CD79b prior to acalabrutinib therapy was associated with increased risk of disease progression on acalabrutinib in patients with CLL. When stratified by pretreatment CD49d surface expression, the CD49d<jats:sup>hi<\/jats:sup> group (defined as \u2265 30% CD49d+\u00a0cells at baseline) showed reduced acalabrutinib\u2010induced lymphocytosis and higher levels of tumor proliferation markers such as CD38 and Ki\u201067 compared with the CD49d<jats:sup>lo<\/jats:sup> group (defined as &lt; 30% CD49d+\u00a0cells at baseline). In summary, CD49d and CD79b are useful predictive markers for CLL progression on acalabrutinib.<\/jats:p><jats:p><jats:bold>Trial Registration:<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link> identifier: NCT02029443<\/jats:p>","DOI":"10.1002\/hon.70008","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T05:42:23Z","timestamp":1735018943000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Molecular Profiling Identifies CD49d and CD79b as Predictive Markers for Acquired Acalabrutinib Resistance in Patients With Chronic Lymphocytic Leukemia"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8528-4860","authenticated-orcid":false,"given":"Elena","family":"Bibikova","sequence":"first","affiliation":[{"name":"Hematology, Oncology R&amp;D 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